PAS-04-072: NEUROVASCULAR MECHANISMS OF BRAIN FUNCTION AND DISEASE

Department of Health
and Human Services (HHS)

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NEUROVASCULAR MECHANISMS OF BRAIN FUNCTION AND DISEASE RELEASE DATE: March 5, 2004 PA NUMBER: PAS-04-072 The R01 portion of this funding opportunity has been replaced by PAS-07-197, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond. March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. Accordingly, the R21 portion of this funding opportunity expires on the date indicated below. Other mechanisms relating to this announcement will continue to be accepted using paper PHS 398 applications until the stated expiration date below, or transition to electronic application submission. A replacement R21 (PAS-06-200) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. EXPIRATION DATE: for R21 Applications: March 2, 2006 Expiration Date for R01 Non-AIDS Applications: November 2, 2006 Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 (NINDS), 93.866 (NIA) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THE PA The goal of this Program Announcement with set-aside funds (PAS) is to invite applications for studying the integration of neurobiological and cerebrovascular mechanisms in the adult, aged and pediatric brain in health and disease. This PAS encourages studies focused on improving our understanding of the dynamic interactions within the neurovascular unit (NVU), a construct consisting of brain microvascular endothelium, glia, neurons and the extracellular matrix that maintains spatial relations among them. Knowledge of these interactions has the potential to stimulate new strategies for basic, translational and clinical research in many neurological disorders, including stroke, vascular dementia, and intracerebral hemorrhage. Among the challenges to be addressed are: generate new hypotheses and conduct exploratory work on microvessel neuron communication; increase our knowledge about cell-cell signaling and how insults to the endothelium affect parenchymal cell damage, which applies not only to stroke, but may also contribute to understanding neurological disorders in which vascular changes are observed; and, elucidate mechanisms by which neurons communicate with blood vessels through interactions with non-neuronal cells in the microenvironment including endothelium, pericytes, astrocytes, oligodendrocytes and microglia. RESEARCH OBJECTIVES Background Stroke is widely recognized as a major cause of premature mortality and disability, particularly cognitive and motor impairment. Significant progress has been made in dissecting the molecular pathways of excitotoxicity, oxidative stress and apoptosis in ischemic neuronal cell death. However, translation of these laboratory results into clinically effective stroke treatments remains a major challenge for the stroke community today. To address this issue and the prediction that strokes will increase in our aging population, Congress requested the NINDS to develop a stroke research action plan. The leadership of the Institute responded by implementing a major planning effort called the Stroke Progress Review Group (SPRG). The SPRG identified research on the cellular and functional interactions among the capillaries, glia, and neurons of the brain, termed the "neurovascular unit (NVU), as a top priority. The term "neurovascular unit" is intended to focus attention on the interactions among cerebral blood vessels and the neurons they serve. It refers to the composite of the endothelium, extracellular matrix, astrocytes, pericytes and neurons. The term emphasizes the roles that the microvessel and the vascular compartment play in neuronal responses and emphasizes the dynamics of vascular, cellular and matrix signaling in both the grey and white matter. The NVU strategy looks beyond the single cell for a more integrative answer to ischemic brain damage which may be closer to modeling the clinical reality. After ischemia, perturbations in neurovascular functional integrity initiate several cascades of injury. Upstream signals such as oxidative stress, together with neutrophil and/or platelet interactions with activated endothelium, upregulate matrix metalloproteinases (MMPs), plasminogen activators and other proteases, which degrade matrix and lead to blood brain barrier leakage. Inflammatory infiltrates through the damaged blood brain barrier amplify brain tissue injury. Additionally, disruption of cell-matrix homeostasis might also trigger cell death pathways in both vascular and parenchymal compartments. Excitotoxicity has also been shown through tissue plasminogen activator (tPA)-mediated interactions with the NMDA (N-methyl-D-aspartate) receptor, which augment ionic imbalance and cell death. Neuronal cell death ultimately underlies ischemic brain injury and the neurovascular unit concept suggests that proximal triggers in endothelium play an important upstream role. Refocusing research on how endothelial injury affects parenchymal damage applies not only to stroke, but may also contribute to understanding neurodegenerative disorders, like vascular dementia, Alzheimer’s disease, MS and ALS, in which vascular changes are observed. Studying neurovascular changes as a function of aging may also help in understanding how the NVU contributes to age-related changes in brain structure and function, particularly motor and cognitive decline. Thrombolysis trials firmly establish the idea that timely reperfusion can salvage the ischemic brain. The efficacy of hypothermia so far confirms that multiple molecular cascades are indeed operational in human brain and that neuroprotection is an achievable goal. Ultimately, combination therapies that target the entire neurovascular unit, promote cell survival mechanisms and extend the therapeutic time-window for reperfusion therapy will provide the required opportunities to meet the challenges for stroke. Moreover, developing therapies that maintain proper NVU function or that prevent age-associated alterations in the NVU may find use in the prevention or treatment of age-related neurodegenerative or neurovascular conditions. The Stroke Progress Review Group is responsive to Congressional requests for planning in this area. The scientific support for this initiative can be found in the report on the NINDS homepage at: (http://www.ninds.nih.gov/funding/areas/neural_environment/index.htm) Scope This PAS is intended to achieve a better understanding of the integration of cerebrovascular and brain mechanisms in the development of the healthy brain, in the maintenance of function in the aging brain, and in neurological disorders and stroke. A major goal is to improve our knowledge of cell-cell communication within the NVU and how vascular function may contribute to the initiation and/or progression of neurological diseases over the lifespan. Developing new approaches for targeting the NVU, based on biological considerations, in order to improve potential combination or multi-targeted treatments for stroke and other neurological disorders is encouraged. Research areas appropriate for this announcement and applicable to either healthy or disease conditions include, but are not limited by the following examples: o Develop and characterize in vivo and in vitro models that reflect the unique features of neurovascular communication in the brain under normal, aging, and disease conditions. Existing in-vivo models, such as those for stroke or neurodegenerative diseases, may also prove useful for studying the cellular dynamics of the NVU. Studies that validate in vitro results with in vivo models are encouraged. o Examination of the genes and proteins that are uniquely expressed by the NVU and mechanisms by which brain cells regulate endothelial cell gene expression and visa versa. This includes endothelial cell changes that occur in response to neurological disease, for example, characterization of molecular signatures for disease diagnosis and targeting. o Identify pattern-specific gene and protein expression within the NVU to provide a platform for further investigations on integrating brain-vascular biology as it pertains to conditions such as angiogenesis, cell adhesion, antigen presentation, metastasis, and local inflammation. o Explore the genesis and regulation of the NVU, its stem cell origins and the interactions of microvessel networks in the regions of the CNS with developing neurons and in areas of adult neurogenesis. o Identify signal transduction pathways of brain and capillary endothelial cells in the regulation of the extracellular matrix under normal and disease conditions. o Identify regional diversity of NVU properties within the brain and the microvasculature throughout the lifespan. Develop treatment strategies that target the unique biological properties of the NVU in contrast to single cell targeting. o Identify changes in NVU integrative functions in vivo and/or in-situ using imaging approaches. o Explore the cell-cell interactions among the cellular and matrix elements of the NVU. Examine cell-cell communication in tri-cultures with matrices of different composition. o Examine the plasticity of the NVU and the changes in cell-cell and cell- matrix signaling throughout the lifespan. Applications should focus on neurological disorders relevant to the research missions of NINDS and/or NIA. A partial list of diseases of interest to NINDS is given in Appendix A of the planning document Neuroscience at the New Millennium; http://www.ninds.nih.gov/about_ninds/plans/strategic_plan.htm). These include neurological disorders (e.g. stroke, brain tumors, brain and spinal cord trauma, epilepsy, multiple sclerosis, neuro-AIDS, vascular dementia, ALS, Parkinson’s disease and Alzheimer's disease). NIA is interested in age- related neurodegenerative disorders, such as Alzheimer’s disease; impairments in cognitive, motor and sensory functions; and mechanisms underlying changes in neuroplasticity across the lifespan. Research areas relevant to the mission of the NIA can be found at: http://www.nia.nih.gov/ResearchInformation/ ExtramuralPrograms/NeuroscienceOfAging/Research+Areas.htm MECHANISMS OF SUPPORT A large amount of basic research is needed to significantly change how we translate neuroscience research. This PAS is focused on stimulating new concepts on integrating cerebrovascular communication with neurons through the exploratory/developmental grant (R21) and the R01 mechanisms. This PAS will remain active for 3 years to address the many gaps in our knowledge of how the NVU may function in health and disease and the time needed to explore this critically important research area. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. The R21 mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models or applications that could have major impact on a field of biomedical, behavioral, or clinical research. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications. R21 applications may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two-year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year. This PAS uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Competing continuation applications submitted in response to this PAS will compete with all investigator-initiated applications and be referred and 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. The earliest anticipated award date is June 1, 2004. FUNDS AVAILABLE NINDS and NIA have set aside $1,100,000 in total costs per year. NINDS will use set-aside funds for applications sent in response to this program announcement that score outside the NINDS payline (see NINDS Funding Strategy http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on the overall scientific merit of the applications and the availability of funds throughout the duration of this solicitation (3 years). NIA will consider programmatic priority, as reflected in this PAS, and scientific merit in using set-aside funds for applications assigned to it in response to this PAS. The total project period for an application submitted in response to this PAS may not exceed 5 years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the Institute provide support for this program, awards pursuant to this PAS are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAS and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: Direct inquiries regarding scientific/research issues to: Dr. Thomas P. Jacobs NINDS Neuroscience Center, Rm 2112 6001 Executive Blvd. Bethesda, MD 20892-9527 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: jacobst@ninds.nih.gov Dr. Bradley C. Wise NIA Gateway Building, Suite 350 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@nia.nih.gov Direct inquiries regarding financial or grants management matters to: Ms. Tina Carlisle Grants Management Branch NINDS 6001 Executive Boulevard, Rm Bethesda, MD 20892 Telephone: (301) 496-3938 Email: carlit@ninds.nih.gov Ms. Linda Whipp Grants and Contracts Management Office NIA 7201 Wisconsin Avenue, Suite 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: WhippL@nia.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. Please note that AIDS related applications have separate receipt dates. SUPPLEMENTAL INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan For R21 applications only, items a d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required for R21 proposals, but may be included if it is available. Please note that a Progress Report is not needed for R21 awards; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that for R21 applications, no more than 5 manuscripts, previously accepted for publication, may be included. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in the modular grant format. The modular grant 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 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PAS that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PAS will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the appropriate national advisory council or board REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The 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 do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will 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 criteria included in the section on Federal Citations, below). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children 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 Inclusion Criteria in the sections on Federal Citations, below). 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 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PAS will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS 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 DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. See http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, 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 (see 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 PAS 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). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 PAS is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. 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.

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