VIRAL GENETICS IN HIV/CNS DISEASE: IMPLICATIONS FOR PATHOGENESIS RELEASE DATE: March 29, 2002 RFA: RFA-MH-02-012 National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) LETTER OF INTENT RECEIPT DATE: May 15, 2002 APPLICATION RECEIPT DATE: June 12, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA 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 Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Drug Abuse (NIDA) solicit applications for grants to support studies focused on understanding the molecular and viral genetic factors controlling HIV-1 neuropathogenesis in the setting of highly active anti-retroviral therapy (HAART). The objective of this cooperative effort is to foster investigations utilizing genetic approaches to study mechanisms of HIV-1 induced nervous system disease with emphasis on trafficking, cell type specific and regional compartmentalization, viral evolution, functional diversity, establishment of latent reservoirs and the emergence of drug resistance in the central nervous system (CNS) versus other body compartments. RESEARCH OBJECTIVES Background HIV enters the nervous system soon after infection, eventually resulting in a range of mild to severe cognitive, motor and behavioral symptoms. The most severe cognitive impairments have been described from a clinical diagnosis as HIV-associated dementia (HAD). Currently available HAART therapy has reduced the severity of neurological and neurobehavioral dysfunction in infected individuals. However, the drugs used for HAART therapy do not enter the brain efficiently. This presents unique challenges in controlling HIV-1 infection, spread and persistence in the CNS compartment. The dynamics of viral responses in the CNS in terms of trafficking, compartmentalization, viral evolution, emergence of drug resistance and establishment of viral reservoirs in the setting of HAART is not completely understood. In order to assess the potential long-term implications of HAART on neurological disease it is critical to have a thorough understanding of the molecular and viral genetic factors controlling neuropathogenesis. The goal of this initiative is to encourage research using genetic approaches to improve our understanding of HIV-induced nervous system disease in the presence or absence of HAART treatment. The following are examples of research that are encouraged under this RFA. I. Viral Evolution in the CNS. a. Determine if unique viral sequences are associated with neurovirulence b. Study of the role of viral evolution and trafficking in the establishment of regional genetic heterogeneity of HIV-1 in CNS c. Comparisons of sequences of HIV-strains derived from CNS and other organs for assessment of compartmentalized virus evolution II. CNS Cell type Specific Compartmentalization of HIV Infection. a. Identification and sequence analysis of unique receptors used to infect perivascular and parenchymal macrophages, microglia, endothelial cells and astrocytes b. Assessment of viral sequences that are important in infection and replication in various CNS derived cells (macrophages, microglia, endothelial cells and astrocytes) c. Identification of CD4-independent variants in brain and potential implications in neuropathogenesis III. HIV-1 Molecular Diversity and Resulting Functional Consequences. a. Assessment of molecular diversity of various HIV-1 genes (e.g., Tat, Nef) and resultant functional consequences in CNS b. Correlation of molecular changes of HIV-1 strains derived from demented and non-demented individuals and associated impact on function c. Study of the role of defective/non-infectious envelope in the induction of neurotoxicity as well as in stimulating release of toxic mediators d. Comparisons of the ability of various CNS and non-CNS derived HIV-1 strains to release neurotoxins from glial cells and macrophages and assessment of the relationship, if any, to viral sequences and neurovirulence e. Assessment of differences between HIV-1 envelopes in signaling of macrophages, microglial cells, astrocytes, endothelial cells, and neurons, identification of any relationships between signaling differences, HIV-1 envelope sequence diversity and functional effects. IV. Emergence of Drug Resistance in CNS parenchyma/CSF versus other body compartments. a. Assessment of independent emergence of drug resistance mutations in CNS parenchyma/CSF versus other body compartments b. Sequence analysis of HIV-1 derived from patient populations with discordant control of HIV-1 in CSF and plasma to assess emergence of compartmentalized drug resistance as well as potential reseeding of peripheral compartments V. Use of novel molecular approaches to facilitate studies of HIV induced neuropathogenesis. The heteroduplex-tracking assay is an example of an assay that provides advantages in sampling of HIV populations from various compartments. VI. Studies focusing on the involvement of opiod/cannabinoid systems in the above processes are appropriate. The research examples described above are illustrative and are not meant to be all inclusive. Although research with HIV-1 is the focus of this initiative, studies with animal models such as those using SIV and FIV are also strongly encouraged. MECHANISM OF SUPPORT This RFA will use NIH research project grants (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is December 1, 2002. This RFA uses just-in-time concepts. It also uses the modular and 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. FUNDS AVAILABLE NIMH intends to commit approximately $1,200,000 in FY 2003 to fund three to five new and/or competitive continuation grants in response to this RFA. NINDS will commit $800,000 in FY 2003 to fund two or three new grants that are responsive to this initiative. NIDA plans to fund two or more grants supporting meritoriously applicable research in this area. An applicant may request a project period of up to five years. 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 IC(s) provide support for this program, awards pursuant to this RFA 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 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 inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Jeymohan Joseph, Ph.D. Center for Mental Health Research on AIDS National Institute on Mental Health 6001 Executive Boulevard, Room 6202, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-6100 FAX: (301) 443-9719 Email: jjeymoha@mail.nih.gov Toby Behar, Ph.D. Neural Environment Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Rm 2114A, MSC 9521 Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: behart@ninds.nih.gov Charles Sharp, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: cs107m@nih.gov o Direct your questions about peer review issues to: Michael Kozak, Ph.D. Chief, Extramural Review Branch Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6138, MSC 9608 Bethesda, MD 20892-9608 Telephone: (301) 443-1340 FAX: (301) 594-0702 Email: mkozak@mail.nih.gov o Direct your questions about financial or grants management matters to: Brian Albertini Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-0004 FAX: (301) 443-0219 Email: albertinib2@mail.nih.gov Diana Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov Gary P. Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-849 Email: gf6s@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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: Jeymohan Joseph, Ph.D. Center for Mental Health Research on AIDS National Institute on Mental Health 6001 Executive Boulevard, Room 6202, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301)443-6100 FAX: (301)443-9719 Email: jjeymoha@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. 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. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form 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/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional copies of the application must be sent to: Jean G. Noronha, Ph.D. Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6154, MSC 9609 Bethesda, MD 20892-9609 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-3367 Email: jnoronha@mail.nih.gov APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) 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 CSR 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 already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the participating ICs. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NIMH in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Councils of the participating institutes. 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, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 15, 2002 Application Receipt Date: June 12, 2002 Peer Review Date: July/August 2002 Council Review: October 2002 Earliest Anticipated Start Date: December 1, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS 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 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. 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 Nos. 93.242 (NIMH), 93.853 (NINDS), and 93.279 (NIDA), and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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