GLIAL CELL INFLAMMATORY MECHANISMS OF HIV-1 INDUCED CELL INJURY IN THE NERVOUS SYSTEM RELEASE DATE: March 20, 2003 PA NUMBER: PAS-03-084 EXPIRATION DATE: 1 November 2005, unless reissued National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov) National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 (NINDS), 93.242 (NIMH) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanisms 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 THIS PA The National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) invite applications to promote research into the role of neuroinflammation in the initiation and expansion of cellular injury and death in the context of HIV-1 infection of the central nervous system (CNS). Recent evidence indicates that microglial and astrocytic activation results in the release of excitotoxins, arachidonic acid metabolites, reactive oxygen species, cytokines and chemokines that lead to neurodegeneration and cognitive impairment in HIV-1 infected individuals. The intent of this PAS is to intensify interest and investigator-initiated research, to attract new investigators to this field, and to mobilize interdisciplinary approaches. RESEARCH OBJECTIVES Neurological dysfunction is a devastating complication of HIV-1 infection, affecting an estimated 25% of individuals chronically infected with the virus. Symptoms of dysfunction include cognitive deficits, motor impairment, and behavioral problems. The pathophysiological mechanisms underlying the changes in neurological function are as yet, unresolved, but may include neuroinflammatory responses to HIV-1 infection. The low number of HIV-1 infected cells in the brain does not explain the extent of the neuropathology observed in HIV-1 encephalopathy. Emerging evidence indicates HIV-1 proteins exhibit toxicity to nerve cells only when non-neuronal cells, such as macrophages, microglia, or astrocytes are present. This suggests that indirect mechanisms are important mediators of HIV-1 induced neuronal injury or death. At least two glial cell types appear to participate in CNS inflammation. Microglia, considered to be resident macrophages of the CNS, are a widely distributed cell population within brain parenchyma constituting about 1 to 2% of all cells. Upon activation, microglia release proinflammatory molecules such as cytokines and chemokines, as well as mediators of cell injury such as free radicals. Astrocytes in the brain (which constitute about 50% of all cells) can act as antigen presenting cells, can be induced to express a variety of pro-inflammatory and immune-regulatory molecules, and can interact with immune cells infiltrating the CNS. Astrocytes maintain homeostasis of the neural environment by regulating extracellular pH, modulating ion and neurotransmitter levels in the microenvironment, and regulating the movement of molecules from the vascular compartment into the parenchyma of the CNS by forming an integral component of the blood-brain barrier. In addition, astrocytes and neurons are metabolically coupled. Localized inflammatory processes in the brain may modulate astrocyte function, resulting in changes in the local environment that leave neurons and other cells vulnerable to injury. Future discoveries into mechanisms that regulate neuroinflammation in HIV-1 infected CNS could lead to the development of new treatment strategies for NeuroAIDS. Studies to be funded in response to this PAS could include but are not limited to: o Investigating the role of microglia and astrocytes in the etiology of AIDS dementia. o Advancing studies on cell-cell interactions in the neuroinflammatory cascade. o Investigating the roles of excitotoxicity, the production of nitric oxide, and the production of reactive oxygen species as mechanisms of neuropathogenesis in HIV-1 infection of the CNS. o Defining phenotypic markers which characterize activated microglia and astrocytes in the context of HIV-1 infection of the nervous system. o Delineating the contribution of microglia and astrocytes to the development of inflammation of the HIV-1 infected CNS via antigen presentation or production of specific cytokines and chemokines. o Investigating contributions of perivascular microglia and astrocytes to the entry of blood macrophages into the CNS across the blood-brain barrier. o Investigating the role of HIV-1 proteins in the activation of microglia and astrocytes, or their role in mediating damage to neurons. o Development of animal models of HIV-1 induced neuroinflammation. o Development of assays that use human neurons as targets of HIV-1 induced neuroinflammation. o Delineation of apoptotic pathways involved in the death of CNS cells in the context of HIV-1 infection. o Investigating how neuroinflammation affects astrocytic maintenance of the neural environment. o Investigating mechanisms by which HIV-1 induced inflammatory agents released from activated astroglial and microglial cells can precipitate psychiatric illnesses such as major depression. o Identifying biological mediators of psychiatric illnesses that influence HIV-1 disease progression. o Investigate mechanisms by which peripherally induced inflammatory agents such as cytokines and chemokines influence astroglial and microglial cells and examine the contribution of these responses to the pathogenesis evident in the central nervous system response to HIV-1 infection. MECHANISM(S) OF SUPPORT This PAS will use the NIH R01 and R21 award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The proposed project period during which the research will be conducted should adequately reflect the time required to accomplish the stated goals and should be no more than 5 years for R01 grants. The R21 grants are one-time awards to support innovative, high impact research projects that would either 1) assess the feasibility of a novel avenue of investigation, 2) involve high risk experiments that could lead to a breakthrough in a particular field, or 3) demonstrate the feasibility of new technologies that could have major impact in a specific area. For this PA, participating NIH institutes will use the NINDS guidelines for the R21 mechanism, which can be found at http://www.ninds.nih.gov/funding/r21guidelines.htm. R21 proposals are limited to two years with a maximum of $275,000 direct costs 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 program is appropriate both for new investigators seeking to establish independent research careers and for established investigators wishing to explore new areas of neuroscience or develop novel technologies. 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. FUNDS AVAILABLE NINDS has set aside $1,500,000 total costs in addition to funds available for applications sent in response to this PAS that score within 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). NIMH plans to pay up to $500,000 in total costs in FY 2004 for applications sent in response to this PAS, depending on the overall scientific merit of the applications and the availability of funds. 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 o Faith-based or community-based 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 PA and welcome the opportunity answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Michael Nunn, Ph.D. Neural Environment Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 2118 Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: mn52e@nih.gov Or Kathy L. Kopnisky, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Blvd., Room 6199 Bethesda, MD 20892 Phone: (301) 443-7726 Fax: (301) 443-9719 Email: kkopnisk@mail.nih.gov o Direct your questions about financial or grants management matters to: Michael Loewe Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 3254 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: ml70m@nih.gov Or Brian Albertini Grants Management Branch National Institute of Mental Health 6001 Executive Blvd., Room 6123 Bethesda, MD 20892 Phone: (301) 443-0004 Email: albertib2@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines for AIDS- related grant applications, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a 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 PA 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 PA 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 Receive a written critique. 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 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment 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. Your 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, you 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 your study address an important problem? If the aims of your 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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). 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 CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. 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 PA 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. MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 AMENDMENT "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://grants.nih.gov/grants/stem_cells.htm 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 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 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 PA 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. 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.understand the basic scope 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 PA 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.
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