Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)

Components of Participating Organizations
National Institute on Aging (NIA/NIH), (http://www.nia.nih.gov/)
Office of Research on Women's Health (ORWH/OD/NIH), (http://www4.od.nih.gov/orwh/)

Title: Biology of the Perimenopause: Impact on Health and Aging in Non-Reproductive Somatic and Neuronal Tissues

Announcement Type
New

Request For Applications (RFA) Number: RFA-AG-05-008

Catalog of Federal Domestic Assistance Number(s)
93.866

Key Dates
Release Date: January 27, 2005
Letters of Intent Receipt Date(s): April 18, 2005
Application Receipt Dates(s): May 16, 2005
Peer Review Date(s): August-September, 2005
Council Review Date(s): January, 2006
Earliest Anticipated Start Date: April 1, 2006
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date: May 17, 2005


Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

Section II. Award Information
  1. Mechanism(s) of Support
  2. Funds Available

Section III. Eligibility Information
  1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
  2. Cost Sharing or Matching
  3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
  1. Address to Request Application Information
  2. Content and Form of Application Submission
  3. Submission Dates and Times
    A. Receipt and Review and Anticipated Start Dates
      1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
  4. Intergovernmental Review
  5. Funding Restrictions
  6. Other Submission Requirements

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
 3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations


Part II - Full Text of Announcement


Section I. Funding Opportunity Description

1. Research Objectives

BACKGROUND

Menopause transition and health risks: Compared with the premenopause, the perimenopause is characterized by menstrual cycle irregularities, changes in levels of gonadal steroids, and a tendency for increased risk for specific health problems including cardiovascular (1-3) and cerebrovascular (4) disease, osteoporosis (5-7), declining verbal memory (8), and declining muscle function leading to frailty (9). In young women with menstrual cycle irregularities there is a similar tendency for these increased health risks (1, 10-13). This has led to the hypothesis that having regular menstrual cycles with normal premenopausal hormone levels is in some way protective against risk of these specific health problems and that estradiol 17-ß, a potent, ovarian-derived premenopausal estrogen, is a protective factor. However, recent findings in clinical trials have provided evidence that chronic administration of conjugated equine estrogens with or without medroxyprogesterone does not reduce risk, and may increase risk of impaired cardiovascular and cognitive outcomes, thus shedding doubt on the protective role of estrogen.

Hormone action on non-reproductive tissues: During the natural menopausal transition, the dynamics of the hypothalamic-pituitary-ovarian (H-P-O) axis hormones change dramatically from cyclic to static patterns and levels. Changes in hormone levels and/or dynamics from the highly orchestrated process seen before menopause to more constant hormone exposure after menopause could conceivably affect pathological processes within non-reproductive somatic and CNS tissues.

Estrogen is only one of the H-P-O axis hormones that impacts non-reproductive tissue and declines across the menopause; so do progesterone, testosterone, and inhibins A and B. A number of studies have demonstrated the direct action of ovarian steroids and other H-P-O axis hormones on non-reproductive somatic tissues (14-18). Ligand-independent activation has also been observed for steroid hormone pathways (19-22). Thus, steroid hormone signaling pathways can be activated either directly or indirectly with beneficial or harmful effects. Also, at the perimenopause serum levels of pituitary gonadotropins increase, and glycosylation patterns are altered (23). Furthermore, gonadotropin receptors have been localized on non-reproductive tissues (24, 25) allowing for the possibility of direct biologic effects of elevated gonadotropins in non-reproductive tissues.

Hormone biosynthesis/metabolism in non-reproductive tissues: The regulatory mechanisms and function of steroid hormone synthesis and metabolism in non-reproductive tissues are poorly understood. For example, brain, bone, cardiovascular, and adipose tissues are reported to synthesize and metabolize estradiol-17ß (26-31), but little is known regarding the physiologic function of the local hormone production/metabolism, how these processes are regulated, or age- or menopause-related changes in these processes. Additional research is required on hormone synthesis and metabolism in non-reproductive tissues in order to understand the process that occurs in the development of the pathophysiology associated with the menopausal process in these tissues.

Direct vs indirect hormonal effects: The increased risk for health problems and conditions associated with the menopause could be due to several factors. These might be either direct or indirect. Direct effects could act via altered H-P-O hormonal levels and/or altered hormonal cyclicity on non-reproductive tissues. Indirect effects could be due in part to the effects of altered hormone levels on target tissues resulting in, for example, changes in metabolism and adiposity (32, 33), which in turn could increase risk for menopause-related health problems and conditions. Some combination of both direct and indirect effects could also be responsible for the observed menopause-related increased risk.

Effects of aging: Risk factors for health problems and conditions associated with the menopause increase with age, independent of menopause-related changes in H-P-O axis hormone levels and cyclicity. Levels of non-reproductive systemic hormone levels change drastically with age, such as decreases in growth hormone, IGF-I, and adrenal dehydroepiandrosterone and its sulfate, and increases in insulin, thus altering the hormonal milieu and interacting with H-P-O axis hormone changes associated with the menopause transition. As well there are age-related biological changes, such as increased oxidative and DNA damage, increased protein glycation, increased fraction of senescent cells in tissues, and age-related changes in gene expression patterns. Age-related changes in sensitivity to, and function of, H-P-O axis hormones are reported in non-reproductive tissues (34-37). It is important to distinguish whether changes in underlying biologic processes associated with increased risk for health problems and conditions are associated primarily with aging, menopause, or some combination.

Model systems: Research on human subjects is constrained by the issues of human subjects protection, as well as by practical and financial issues. Thus model systems are recommended for research directly addressing underlying genetic, molecular and cellular biologic mechanisms that connect the human menopause with associated pathophysiology. Model systems that could be employed include isolated human or animal cells, tissues, or biospecimens and whole-body human and animal models that are appropriate to the research questions asked. Two NIA sponsored workshops have addressed the advantages and disadvantages of commonly used or proposed animal models of female reproductive aging. Summaries of those workshops have been published (for non-primate mammals, see ref 38; for non-human primates, see ref 39), and a section of the recent workshop described below – Biology of the Perimenopause: Impact on Health and Aging – also addressed the issue of animal models. Animal species that do not completely model the human menopausal process (e.g., in terms of changes of hormonal levels or dynamics, and/or in terms of postmenopausal life span) might be considered potential models of segments of the human female menopause.

For research utilizing animal models, most prior research has utilized ovariectomized rodent or non-human primate animal models. While ovariectomized animals may be considered appropriate models for the minority of women with surgical menopause, this model does not replicate the natural menopause. Emphasis should be placed on research applicable to the natural menopause in which the H-P-O axis remains intact. Rodent models for which ovarian follicular endowments are modulated by transgenic (40, 41) or chemical (42) means have been described and may be candidates for appropriate models. One major problem with the non-human primate model, where females of some species do experience reproductive aging processes very similar to the human menopause, is the short postmenopausal life span relative to the human female. Thus efforts to lengthen their postmenopausal life span (e.g., by advancing the natural menopause or extending the average lifespan) may enhance their appropriateness to explore the biologic connections between human menopause and the development of menopause-related pathophysiology.

Biology of the Perimenopause: Impact on Health and Aging workshop report: To examine the current state of knowledge and obtain recommendations for future research, the National Institute on Aging (NIA) and the NIH Office of Research on Women's Health (ORWH) sponsored a workshop, Biology of the Perimenopause: Impact on Health and Aging, held May 26-27, 2004 in Bethesda, MD. A summary of the presentations and discussion from that workshop is available at http://www.nia.nih.gov/ResearchInformation/ConferencesAndMeetings/Biology+of+the+Perimenopause+-+Impact+on+Health+and+Aging+Workshop.htm. This workshop addressed four principal questions:

The conclusion from the workshop was that research emphasizing a broader look at underlying biologic mechanisms associated with the impact of the menopausal process on the health of non-reproductive somatic and neural tissues and organ systems applicable to middle-aged women is essential; the workshop also emphasized the importance of developing appropriate model systems to facilitate the exploration of underlying biologic mechanisms.

OBJECTIVES OF THIS RESEARCH PROGRAM

The goal of this RFA is to solicit applications for research studies to better understand underlying biologic mechanisms associated with the increased risk for, or decreased protection leading to, health problems and conditions associated with the menopausal process in middle-aged women. The focus is on a) how H-P-O axis hormone levels and dynamic changes in hormone levels across the menopausal transition affect pathophysiologic processes within non-reproductive somatic and neuronal target tissues, b) the role of steroid hormone biosynthesis and/or metabolism within non-reproductive somatic and neuronal tissues on pathophysiologic processes within these tissues across the perimenopause, and c) the role of aging on these pathophysiologic processes. The H-P-O axis hormones include, but are not limited to, steroid hormones (estrogen, testosterone, progesterone) and their metabolites, as well as peptide hormones (inhibin/activin and gonadotropins). Dynamic changes across the menopausal transition include changing levels and phase relationships among these hormones as women transition from pre- into postmenopause. Aging changes include, but are not limited to, increasing oxidative damage, protein glycation, cell senescence, and genetic instability, as well as age-changes in serum levels of non-reproductive hormones, growth factors, and cytokines. Non-reproductive somatic and neuronal tissues include, but are not limited to, musculoskeletal, cardiovascular, adipose, immune, brain, and cognitive function.

Alternatively, the goals of this RFA may also be understood in terms of current longitudinal observational studies of the human menopausal process. Various studies (see Resources listing below), including the NIH-supported SWAN study, have made or are in the process of making observational connections between hormonal changes across the H-P-O axis during the menopause transition and changes in various organ systems, including cardiovascular, bone, CNS, etc. Thus, the goals of this RFA are to explore the underlying biologic mechanisms connecting these hormonal changes with the various observed (and postulated) pathophysiologic processes.

This RFA is limited to studies addressing the underlying BIOLOGY of endogenous H-P-O axis hormones and their interactions with non-reproductive organ systems. Studies involving clinical trials or therapeutic interventions will NOT be responsive.

Research topics that would be responsive include, but are not limited to:

• MODEL SYSTEMS: development and utilization of appropriate clinical and animal model systems, including cellular and in vitro models, to explore specific H-P-O axis-non-reproductive tissue interactions during the menopausal transition. Concerning animal models, more desirable systems are those with an intact H-P-O axis, rather than ovariectomized, and ones in which aging processes can be explored from early middle-age through advanced ages. Studies that employ alterations of the timing of the menopausal process by physiologically relevant transgenic or chemical means to distinguish effects of menopause from chronologic age are acceptable. It is the responsibility of the applicant to justify the appropriate and meaningful usage of any model system for the specific question(s) to be addressed.

• BIOLOGIC IMPACT OF ALTERED H-P-O AXIS HORMONES AND HORMONAL DYNAMICS RESULTING FROM THE MENOPAUSE TRANSITION ON PATHOPHYSIOLOGIC PROCESSES IN NON-REPRODUCTIVE SOMATIC AND NEURONAL TISSUES: This would examine the effects of changes of levels and/or phase relationships of H-P-O axis secreted hormones, either alone or in combination, across the menopausal transition on non-reproductive somatic and neuronal tissues involved in menopause-related pathophysiology. Relevant questions include, but are not limited to:

a) the consequences of prolonged and/or irregular menstrual cycles;

b) to what extent and by what mechanisms are biologic outcomes regulated by hormone signaling pathways activated by ligand-independent effectors;

c) to what extent and by what mechanisms do H-P-O axis hormonal changes across the menopause transition INDIRECTLY affect pathophysiologic processes in non-reproductive somatic and neuronal tissues. For example, as described under BACKGROUND; “Direct vs indirect hormonal effects”, these hormonal changes affect metabolic processes and the degree of adiposity, which in turn affect pathophysiologic processes in non-reproductive tissues. What are the specific biologic processes and signaling pathways involved in INDIRECT effects of these hormonal changes on pathophysiologic processes?

d) the interactions of H-P-O axis hormonal changes across the menopause transition with age-related changes in non-reproductive hormones or tissue sensitivity to hormones that affect function of non-reproductive somatic and neuronal tissues, as described under BACKGROUND; “Effects of aging”.

• BIOLOGIC IMPACT AND REGULATION OF HORMONE SYNTHESIS/METABOLISM IN NON-REPRODUCTIVE SOMATIC OR NEURONAL TISSUES: As discussed under BACKGROUND; “Hormone biosynthesis/metabolism in non-reproductive tissues”, steroid hormones associated with the H-P-O axis are synthesized and metabolized in non-reproductive tissues. Thus, these tissues would be expected to receive steroid hormone and their metabolites from plasma as well as locally, resulting in autocrine, paracrine, and endocrine mechanisms underlying hormone exposure. Little is known regarding the physiologic function of locally-synthesized/metabolized steroid hormones, how the process is regulated, how the synthesis/metabolism is affected by age, and the relative roles of autocrine/paracrine vs endocrine exposure in middle-aged women during and after the menopausal transition. It is important that the applicant address potential function related to pathophysiologic changes associated with the menopausal process in studies proposed under this bullet, not simply the presence or absence or processes regulating steroid hormone biosynthesis/metabolism in non-reproductive tissues.

RESOURCES AVAILABLE

There are a number of ongoing or completed studies of middle-aged women that may have biospecimen or other resources available for qualified scientific investigators. Some of these studies and their contact information are:

1. Study of Women's Health Across the Nation (SWAN): the study web site is located at: www.edc.gsph.pitt.edu/swan/public; the SWAN biospecimen repository web site is: www.swanrepository.org

2. Seattle Midlife Women's Health Study: http://www.son.washington.edu/departments/fcn/smwhs/

3. Melbourne Women's Midlife Health Project: http://www.psychiatry.unimelb.edu.au/midlife/index.htm

4. Framingham Heart Study: http://www.nhlbi.nih.gov/about/framingham/

5. Baltimore Longitudinal Study of Aging (BLSA): http://www.grc.nia.nih.gov/branches/blsa/blsa.htm

6. Cardiovascular Health Study: http://www.jhsph.edu/comstockcenter/chs.html

7. Wisconsin Longitudinal Study: http://www.ssc.wisc.edu/~wls/

Additional potential resources include the following:

1. NIA virtual biospecimen repository: http://www.nia.nih.gov/ResearchInformation/ScientificResources/Repository.htm

2. NIA database of longitudinal studies: http://www.nia.nih.gov/ResearchInformation/ScientificResources/LongitudinalStudies.htm

3. Non-human primate resources: http://www.ncrr.nih.gov/ncrrprog/cmpdir/PRIMATES.asp;

4. NIA non-human primate aging set-aside colony: http://www.nia.nih.gov/ResearchInformation/ScientificResources/

If specimens or unpublished data are to be utilized from any of these studies, details on the proposed collaboration and a letter of approval for use of these specimens or unpublished data from the Principal Investigator of the resource or his/her representative should be included in the application.

REFERENCES:

1. Merz CNB, Johnson BD, et al., Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol 41: 413-419, 2003;

2. Camper-Kirby D, Welch S, et al., Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 88: 1020-1027, 2001;

3. Celermajer DS, Sorensen KE, et al., Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24: 471-476, 1994;

4. McCullough LD and Hurn PD, Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab 14: 228-235, 2003;

5. Garnero P, Sornay-Rendo E, et al., Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11: 337-349, 1996;

6. Slemenda C, Hui SL, et al., Sex steroids and bone mass. A study of changes about the time of menopause. J Clin Invest 80: 1261-1269, 1987;

7. Recker R, Lappe J, et al., Characterization of perimenopausal bone loss: a prospective study, J Bone Miner Res 15: 1965-1973, 2000;

8. Kramer JH, Yaffe K, et al., Age and gender interactions on verbal memory performance. J Internat Neuropsychological Soc 9: 97-102, 2003;

9. Bandinelli S, Lauretani F, et al., Understanding the physiological and functional consequences of menopause: the PROSALMEN study. Aging Clinical and Experimental Res 14: 170-177, 2002;

10. Solomon CG, Hu FB, et al., Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 87: 2013-2017, 2002;

11. Chen LD, Kushwaha RS, et al., Effect of naturally reduced ovarian function on plasma lipoprotein and 27-hydroxycholesterol levels in baboons (Papio sp.). Atherosclerosis 136: 89-98, 1998;

12. Prior JC, Vigna YM, et al., Spinal bone loss and ovulatory disturbances. N Engl J Med 323: 1221-1227, 1990;

13. Tomten SE, Falch JA, et al., Bone mineral density and menstrual irregularities. A comparative study on cortical and trabecular bone structures in runners with alleged normal eating behavior. Int J Sports Med 19: 92-97, 1998;

14. Chu MC, Rath KM, et al., Elevated basal FSH in normal cycling women is associated with unfavorable lipid levels and increased cardiovascular risk. Human Reproduction 18: 1570-1573, 2003;

15. Sowers MR, Finkelstein JS, et al., The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN. Osteoporosis International 14: 44-52, 2003;

16. Bowen RL, Verdile G, et al., Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-ß precursor protein and amyloid-ß deposition. J Biol Chem 279: 20539-20545, 2004;

17. Gaddy-Kurten D, Coker JK, et al., Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 143: 74-83, 2002;

18. Karas RH, van Eichels M, et al., A complex role for the progesterone receptor in the response to vascular injury. J Clin Invest 108: 611-618, 2001;

19. Ohtake F, Takeyama K et al., Modulation of oestrogen receptor signaling by association with the activated dioxin receptor. Nature 423: 545-550, 2003;

20 Ciana P, Raviscioni M, et al., In vivo imaging of transcriptionally active estrogen receptors. Nature Med 9: 82-86, 2003;

21. Cenni B and Picard D, Ligand-independent activation of steroid receptors: new roles for old players. Trends Endocrinol Metab 10: 41-46, 1999;

22. Blaustein JD, Minireview: Neuronal steroid hormone receptors: they're not just for hormones anymore. Endocrinology 145: 1075-1081, 2004;

23. Wide L and Naessen T, 17 beta-oestradiol counteracts the formation of the more acidic isoforms of follicle-stimulating hormone and luteinizing hormone after menopause. Clin Endocrinol 40: 783-789, 1994;

24. Rao SC, Li X, et al., Human chorionic gonadotropin/luteinizing hormone receptor expression in the adult rat spinal cord, Neurosci Lett 336: 135-138, 2003;

25. Rao ChV, Zhou XL, and Lei ZM, Functional luteinizing hormone/chorionic gonadotropin receptors in human adrenal cortical H295R cells, Biol Reprod 71: 579-587, 2004;

26. Grohe C, Kahlert S, et al., Expression of oestrogen receptor α and ß in rat heart: role of local oestrogen synthesis. J Endocrinol 156: R1-R7, 1998;

27. Diano S, Horvath TL, et al., Aromatase and estrogen receptor immunoreactivity in the coronary arteries of monkeys and human subjects. Menopause 6: 21-28, 1999;

28. Simpson E, Rubin G, et al., The role of local estrogen biosynthesis in males and females. Trends Endocrinol Metab 11: 184-188, 2000;

29. Simpson ER and Davis SR, Minireview: Aromatase and the regulation of estrogen biosynthesis – some new perspectives. Endocrinology 142: 4589-4594, 2001;

30. McCullough LD, Blizzard K, et al., Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci 23: 8701-8705, 2003;

31. Dubey RK, Tofovic SP and Jackson EK, Cardiovascular pharmacology of estradiol metabolites. J Pharmacol Expr Ther 308: 403-409, 2004;

32. Carr MC, The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 88: 2404-2411, 2003;

33. Ferrara CM, Lynch NA, et al., Differences in adipose tissue metabolism between postmenopausal and perimenopausal women, J Clin Endocrinol Metab 87: 4166-4170, 2002;

34. Wilson ME, Rosewell KL, et al., Age differently influences estrogen receptor-alpha and estrogen receptor-beta gene expression in specific regions of the rat brain. Mech Ageing Dev 123: 593-601, 2002;

35. Chatterjee B and Roy AK, Changes in hepatic androgen sensitivity and gene expression during aging. J Steroid Biochem Mol Biol 37: 437-445, 1990;

36. Khalyfa A, Klinge CM, et al., Transcription profiling of estrogen target genes in young and old mouse uterus. Exp Gerontol 38: 1087-1099, 2003;

37. Chakraborty TR, Hof PR, et al., Stereologic analysis of estrogen receptor alpha expression in rat hypothalamus and its regulation by aging and estrogen. J Comp Neurol 466: 409-421, 2003;

38. Bellino FL, Nonprimate animal models of menopause: a workshop report. Menopause 7: 14-24, 2000;

39. Bellino FL and Wise PM, Nonhuman primate models of menopause workshop. Biol Reprod 68: 10-18, 2003;

40. Danilovich N, Javeshghani D, et al., Endocrine alterations and signaling changes associated with declining ovarian function and advanced biological aging in follicle-stimulating hormone receptor haploinsufficient mice. Biol Reprod 67:370-378, 2002;

41. Perez G, Robles R, et al., Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 21:200 -203, 1999;

42. Mayer LP, Devine PJ, et al., The follicle-deplete mouse ovary produces androgen. Biol Reprod 71: 130-138, 2004.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


1. Mechanisms of Support

This funding opportunity will use the R21 and R01 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time concepts. It also uses the modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/modular/modular.htm).


2. Funds Available

The NIA and ORWH intend to commit approximately $2.5M dollars in FY 2006 to fund 4-6 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs up to $250,000 dollars per year.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIA and ORWH provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-004.html.


Section III. Eligibility Information


1. Eligible Applicants


1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

This program does not require cost sharing.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing


3. Other-Special Eligibility Criteria

There are no other specific eligibility criteria, and applicants may submit as many scientifically different applications as they wish for consideration under this RFA.

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.


2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.


3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: April 18, 2005
Application Receipt Date(s): May 16, 2005
Peer Review Date: August-September, 2005
Council Review Date: January, 2006
Earliest Anticipated Start Date: April 1, 2006


3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:


Frank Bellino, PhD
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Ave.
Gateway Building, Suite 2C231
Bethesda, MD 20892-9205
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: bellinof@mail.nih.gov


3.B. Sending an Application to the NIH


Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. Personal deliveries of applications are no longer permitted.


3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIA . Incomplete and non-responsive applications will not be reviewed. If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm (see also Section VI. 3. Reporting).

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.


6. Other Submission Requirements

Principal Investigators on grants resulting from this RFA must participate in an annual workshop as convened by the NIA for updates and exchange of information related to the projects supported by these grants. In the event the PI is unable to attend, a mutually acceptable designee may be agreed upon by the PI and NIA staff to participate. Travel to this annual workshop, expected to be in Bethesda, MD, should be included in the budget request in the application.

Specific Instructions for Modular Grant applications.

Applications must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Applicants must use the currently approved version of the PHS 398. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

Plan for Sharing Research Data
N/A

Plan for Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information



1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIA . Incomplete and/or non-responsive applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by CSR in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

2. Approach. Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

3. Innovation. Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

4. Investigators. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?


2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women and Minorities in Research: The adequacy of plans to include subjects from all racial and ethnic groups (and subgroups), as appropriate for the scientific goals of the research, will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.


2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data
N/A

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.


3. Anticipated Announcement and Award Dates
N/A

Section VI. Award Administration Information


1. Award Notices


After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

The NGA will be sent by email to the Business Official with a copy to the Principal Investigator.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Frank Bellino, PhD
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: bellinof@mail.nih.gov

Sherry Sherman, PhD
Geriatrics and Clinical Gerontology Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone: (301) 435-3048
FAX: (301) 402-1784
Email: shermans@mail.nih.gov

Andrew Monjan, PhD
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 350
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email: monjana@mail.nih.gov

Lisa Begg, Dr.P.H., R.N.
Director of Research Programs
Office of Research on Women's Health
DHHS/NIH/OD
Bethesda, MD. 20892
Telephone: (301) 496-7853
FAX: (301) 402-1798
Email: beggl@od.nih.gov

2. Peer Review Contacts:

Sooja K. Kim, PhD
Chief, Endocrinology, Metabolism, Nutrition and Reproductive Sciences IRG
Center for Scientific Review, NIH
Rockledge 2, Room 6182
6701 Rockledge Drive
Bethesda, MD 20892-7892
Telephone: (301) 435-1780
FAX: (301) 480-2065
Email: KIMS@CSR.NIH.GOV


3. Financial or Grants Management Contacts:

Deborah Stauffer
Lead Grants Management Specialist
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
FAX: (301) 402-3672
Email:stauffed@mail.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

Public Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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