Full Text DK-97-007 EXPLORATORY GRANTS IN CHRONIC RENAL FAILURE IN CHILDREN NIH GUIDE, Volume 26, Number 2, January 17, 1997 RFA: DK-97-007 P.T. 34, AA Keywords: 0715133 National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 18, 1997 Application Receipt Date: April 18, 1997 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) recognizes the need to enhance research activities in Pediatric Nephrology. The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the NIDDK invites Exploratory Research Project Grant Applications (R21s) to encourage and facilitate studies designed to develop and/or apply new promising experimental tools to the understanding of the pathophysiology and pathogenesis of events resulting in chronic renal failure and its complications, in children. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications Exploratory Grants in Chronic Renal Failure in Children, is related to the priority area of chronic disabling diseases and food safety. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone (202) 512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public or private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) Exploratory/Developmental Research Project Grant (R21) Award. The total requested project period for applications submitted in response to this RFA may not exceed two years. The requested budgets may not exceed $50,000 (Direct Costs) per 12-month budget period. The anticipated award date will be September 30, 1997. This RFA is a one-time solicitation. If the NIDDK determines that there is a sufficient continuing program need, a request for applications will be announced. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE A total of $500,000 in total costs for each of two years will be committed by the NIDDK to fund applications submitted in response to this RFA. It is anticipated that approximately five to seven awards will be made. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES The primary objective of this solicitation is to invite Exploratory Research Project Grant Applications from members of the diverse pediatric research community with research interest, technology, tools and strategies that could be brought to bear on problems relevant to chronic renal failure in children. In order to meet these objectives, this solicitation is put forward to encourage and facilitate the development of exploratory research protocols focused on the pathophysiology and pathogenesis of chronic renal failure in children. The final aim is directed towards the enhanced understanding of the underlying mechanisms leading to chronic renal failure and its complications in children in a combined effort to reduce or eliminate its causes, control disease progression and provide pediatric patients with new and optimal management and interventions. Background Chronic renal disease (CRD) and renal failure in pediatric patients represent a significant problem; the clinical care and attendant services required to manage these patients are the most difficult, time consuming and frustrating endeavors for patients, their families, and treating pediatric nephrologists. Furthermore, when renal replacement therapies are needed, these must be individually tailored to each patient and continuously adapted to meet the special requirements of the growing and developing patient. Progressive renal disease occurs in all age groups resulting from varying underlying causes, recognized as distinct according to the different age-categories involved. Congenital structural malformations, including vesicoureteral reflux, obstruction, hypoplasia and dysplasia, represent the principal underlying causes of end-stage renal disease (ESRD) particularly in the very young child. Added to these, older children also develop chronic renal failure (CRF) resulting from glomerular and tubulointerstitial disease, immune complex disease, hemolytic uremic syndrome, IgA nephropathy, focal segmental sclerosis, hereditary nephropathies, etc. The majority of these disease entities remain mechanistically mysterious. Diabetic nephropathy, so frequently underlying ESRD in the adult population, does not result in CRF in childhood. Nevertheless, most patients with diabetes who develop ESRD in their 20s and 30s, are those whose diabetes presented during childhood or early adolescence. In children, as in adults, renal disease progression occurs even when the primary renal insult has been corrected, treated, or become inactive. Adaptive mechanisms may play an important role in the ongoing process. The similar histologic appearance of chronic renal diseases, which is independent of the initial lesion, represents further evidence that such progressive pathway may be common to all. Regardless of where in the kidney the insult occurs, the structural hallmark of progressive failure is the development of scar tissue, through fibrinogenesis. The biologic mediators of scar formation in the glomerulus have been actively examined and some of the biological mediators which regulate these processes are currently under active investigation. Research continues to focus on growth factors and cytokines which mediate mesangial cell proliferation and the production of extracellular matrix. Treatment of experimental models with agents that block these growth factors have provided new insights into disease pathogenesis and future management. During the past decade, dramatic developments have unfolded in the field of molecular genetics and allied disciplines, allowing for the application of powerful tools and strategies to the investigation of kidney diseases. These same tools need to be more forcefully applied to research focused on renal diseases affecting children. A few selected examples are listed to highlight research progress and opportunities. Included, among many others, are the following recent accomplishments: o Specific mutations have been demonstrated in the collagen COL4A5 gene in patients with Alport's Syndrome. o Molecular alterations associated with the alpha 3 chain of type IV collagen are implicated in the development of Goodpasture's Syndrome, in humans. o The Wilm's tumor suppressor gene WT1, has been identified. Germline WT1 mutations predispose to Wilm's tumor and are often associated with urogenital anomalies. o The cystinuria gene has been mapped to chromosome 2, subregion 2p21, and three distinct phenotypes for cystinuria have been described. The identification of four novel mutations shall serve to complement the measurements of cystine excretion in the selection of patients with high risk of nephrolithiasis, for anticipatory prevention. o The congenital nephrotic syndrome (CNS) locus has been assigned to chromosome 19q12-q13.1 on the basis of linkage analysis in Finnish families; the linkage of the CNS locus to the same chromosomal region was also confirmed in non-Finnish CNS families. CNS is inherited as an autosomal recessive trait and it has been postulated that the primary defect could be a structural and functional defect in the glomerular basement membrane. o In IgA nephropathy, a deletion (D) polymorphism of a fragment of a 287-bp fragment of intron 16 of the angiotensin converting enzyme (ACE) gene, has been recently found to have a significant association with progressive deterioration of renal function. The association of hypertension and mild initial reduction of renal function, as risk factors for progression, suggest that the presence of the DD ACE genotype may shift IgAN from mild to severe, and nephropathy from subclinical to overt. It is suggested that the presence of proteinuria may act as a risk factor for disease progression and renal failure, conceivable because proteinuria and progression share the same genetic risk factor, namely the D polymorphism of the ACE gene. o Concerning complications resulting from CRF, in recent years, the treatment option of recombinant human GH (rhGH) has been successful in stimulating growth in children with various degrees of CRF. Despite this treatment, growth retardation remains one of the major obstacles to successful rehabilitation of children and adolescents with CRF. The pathogenesis of uremic growth failure is only partially understood and it is viewed as resulting from several interrelated processes, all contributing to growth impairment in the uremic child. Recombinant human growth factor (rhIGF-I) has been used in combination with rhGH, and has shown a synergistic effect, improving total nitrogen retention in calorically deprived subjects and stimulating linear growth in children with GH receptor defects. This growth factor may offer promise in the treatment of selective growth disorders and protein catabolic states. o The Final Report of the Growth Failure in Children with Renal Disease Study has been published. The data confirmed that once glomerular filtration rate (GFR) falls to less than 50% of normal, an elevated serum PTH level can be expected; both calcitriol and dihydrotachysterol were found to be equally potent in suppressing PTH elevation. Despite research progress and the evidence of the level of productivity and opportunities, many fundamental aspects of the pathogenesis and pathophysiology of the underlying conditions as well as the adaptation to CRF are incompletely understood, unknown, or remain unexplored in pediatrics and require immediate research attention. Therefore, research efforts should continue, and application of the most up to date research tools must be encouraged to be able to make a difference in the overall prevention of renal disease progression as well as in improving the management of the severe complications resulting from CRF in children. This is the focus of the present RFA. Research Goals and Scope It is the intent of this solicitation to invite applications from investigators of the diverse pediatric research community with research interest, technology and specific strategies, who wish to apply their expertise: (i) to elucidate and enhance the current understanding of the pathogenesis and pathophysiology of CRF in children, focusing primarily on events occurring at the cellular and molecular levels; (ii) to identify, characterize, or develop experimental models, faithful to pediatric chronic renal disease, to help in the understanding of the fundamental events leading to renal disease progression and CRF; (iii) to identify interventions that could lead to improvements in the management and outcome of CRF in children. This special program should encourage interdisciplinary collaboration in the basic disciplines to stimulate and facilitate fundamental research work; research applications can also be more narrowly focussed from one predominant discipline. Highly encouraged is the application of promising new experimental tools to the understanding of mechanisms and events leading to CRF and its complications in pediatrics. Examples of pediatric CRF-related topics illustrating areas which would be considered within the intent of this solicitation, and therefore responsive to, this RFA, are listed. These examples are meant, only, to provide a broad direction and should not be considered restrictive: o Studies addressing the biology of kidney development and differentiation with emphasis on molecular events resulting in abnormalities which may lead to the development of CRF. o Investigation of the inflammatory and immunologic processes and the genetic environment factors responsible for glomerular or tubulointerstitial injury perceived as contributors to the development of progressive renal disease and CRF in children. o Identification and characterization of experimental models faithful to pediatric chronic renal disease and CRF. These experimental models should be ideally suited for the detailed evaluation of events occurring at the cellular, molecular or genetic levels, responsible for the ultimate development of CRF. o Elucidation of the pathogenesis and pathophysiology of relevant complications resulting from, or inherent to CRF in children. o Identification and characterization of early markers of renal disease severity in children. o Identification of novel approaches to improve the immediate and long-term outcome of pediatric CRF. It is hoped that a better understanding of events occurring at the cellular and molecular levels with new technologies and investigative approaches, which have already proven extraordinarily useful in genetics, immunology, and allied disciplines, should enhanced the understanding of the pathophysiologic events, should result in a better understanding of the basic mechanisms leading to chronic renal disease, in pediatrics and help in the development of preventive strategies to prevent or improve the management and outcome of CRF in children. Investigators are not limited to the above examples of research focus, and are encouraged to propose other approaches that are appropriate to Exploratory Research Grants, and to the requirements of this RFA. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as subjects in Clinical Research", which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 18, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NIDDK staff to estimate the potential review workload and avoid possible conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS 37-F - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594 8885 FAX: (301) 480 3505 APPLICATION PROCEDURES The research grant application form PHS-398 (rev. 5/95) is be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, e-mail: ASKNIH@odrockm1.od.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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 under item 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist plus three signed, exact photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent under separate cover to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS 37-F - MSC 6600 Bethesda, MD 20892-6600 Applications must be received by April 18, 1997. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS 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 the NIDDK in accordance with NIH peer review procedures. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG 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 review cycle. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the national advisory council. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator and the official signing for the applicant organization will be notified. REVIEW CRITERIA o Scientific and technical merit criteria specific to the objectives of the RFA. o Scientific, technical, or medical significance and originality of proposed research. o Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research. o Qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research. o Availability of resources necessary to perform the research. o Appropriateness of the proposed budget and duration in relation to the proposed research. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. o For applications involving activities that could have an adverse effect upon humans, animals, or the environment, the adequacy of the proposed means for protecting against or minimizing such effects. AWARD CRITERIA The anticipated date of award is September 30, 1997. Award criteria will include the scientific merit of the application as determined by peer review, availability of funds, and programmatic priorities. Schedule Letter of Intent Receipt Date: March 18, 1997 Application Receipt Date: April 18, 1997 Initial Review: July 1997 Second Level Review: September 17-18, 1997 Anticipated Award: September 30, 1997 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Gladys H. Hirschman, M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-13 - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: gladys_hirschman@nih.gov Inquiries regarding fiscal matters may be directed to: Aretina D. Perry Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-38B - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8862 Email: perrya@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849 and 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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. .
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