RFA-AA-02-008: EFFECTS OF ALCOHOL ON HIV INVASION ACROSS THE BLOOD BRAIN BARRIER OR PLACENTAL BARRIER

Department of Health
and Human Services (HHS)

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EFFECTS OF ALCOHOL ON HIV INVASION ACROSS THE BLOOD BRAIN BARRIER OR PLACENTAL BARRIER Release Date: October 30, 2001 RFA: RFA-AA-02-008 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov) Letter of Intent Receipt Date: December 28, 2001 Application Receipt Date: January 23, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE This RFA intends to encourage innovative research leading to the development of new approaches, technologies, and methods to examine the effects of ethanol on HIV invasion across the blood brain barrier (BBB) or the placental barrier (PB). Alcohol is a common substance used by HIV infected individuals. Evaluation of the effects of ethanol exposure on HIV translocation across the BBB and PB is necessary before intervention strategies can be developed. Research in this under-explored area is needed to understand how the ingestion of alcohol modifies these barriers. In particular, research proposals may be designed to increase understanding of how ethanol consumption may alter physical and immunological properties of the blood- brain or placental barriers, with special attention to how anti-retroviral therapies for HIV could be affected. Mechanisms for the passage of cell-free virus through paracellular and transcellular routes and transmigration of HIV-infected leukocytes across the barriers may be investigated. The culturing and manipulation of these specialized cells are likely to be of great benefit and potential clinical significance for the treatment of HIV- related disease among alcohol abusers. The potential for this exploratory work, i.e. developing relevant in vitro models of the BBB and PB, may have a direct impact on the amelioration of the neurodegenerative pathology associated with alcohol and HIV synergism or the prevention of the perinatal transmission of HIV. 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 Request for Applications (RFA), Title of 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/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigator. MECHANISM OF SUPPORT This RFA will primarily use the NIAAA exploratory/developmental (R21) award mechanism. In addition, R01 applications will be accepted if they are within the scope of the announcement to develop new approaches, technologies, tools, or methods, and do not exceed $250,000 per year in direct costs for a period of up to 3 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA- 99-131, NIAAA Exploratory/Developmental Grant Program, http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is July 1, 2002. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE It is estimated that up to $1,000,000 will be available in FY 2002 to fund 6 to 8 new and/or competitive continuation grants in response to this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. The award of grants pursuant to this RFA is contingent upon the availability of funds for this purpose. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES NIAAA encourages the submission of highly innovative research applications focusing on the development of in vitro blood brain barrier and placental barrier models. It is the goal of this announcement to develop and utilize new technology to learn how alcohol use might alter the nature of the blood brain barrier to promote development of HIV-associated dementia, or how alcohol use might alter the placental barrier to increase susceptibility to HIV infection in the fetus. Relevant in vitro blood brain barrier and placental barrier models may include static transwell, endothelial/organotypic brain slice cultures, or perfusion/hollow fiber models. Background Information on the Blood Brain Barrier: The human immunodeficiency virus (HIV) associated dementia (HAD) is thought to originate as virus- infected monocytes infiltrate into the brain and cause neurologic disease. The mechanism(s) for monocyte penetration across the blood-brain barrier (BBB) remains ill defined but is likely to involve stimulation of transmigration by chemokines secreted by astrocytes, endothelial cells and the monocytes themselves. Many questions about this process, and its relation to immune deterioration and pathogenesis, remain to be investigated. NIAAA is particularly interested in contributing to efforts to expand awareness of how alcohol abuse and alcoholism affects human health and can complicate the illness in those who suffer from HIV and their children. Alcohol has been identified as a cofactor in HIV disease. Since alcohol is a commonly used drug in HIV-infected persons, evaluation of the exacerbating effects of ethanol on HIV neuroinvasion is important and necessary before an appropriate therapeutic intervention strategy can be designed. Moreover techniques for isolation and culture of brain endothelial cells could be of broad benefit for both HIV-related studies and neuropathology in general. Here we attempt to stimulate research which focuses more specifically on learning about how alcohol use might alter the nature of the BBB and could promote development of HAD. Alcohol could cause increase in viral load, change in membrane permeability or transmigration and/or reduced immunological function. Any increase in the titer of viremia caused by alcohol or any change in the titer caused by anti-retroviral therapy may have profound effects on the future course of HIV disease. Some of the questions that the investigator may seek to answer include: - How does the combination of alcohol and HIV restructure microvascular endothelial cells? - How may permeability to serum proteins be effected? - Will rates of migration of mononuclear cells increase across the BBB? - What is the impact of alcohol"s immunosuppressive effects? - What is the effect of alcohol on T-cell maturation? Background Information on the Placental Barrier: The placenta provides a barrier between the maternal and fetal circulations but its role in HIV transmission remains unclear. The placenta consists of a vast array of villi which are bathed directly in circulating maternal blood which is thereby in extensive and intimate contact with fetal tissues. Underlying the villi is a continuous epithelium generated from and maintained by a layer of trophoblastic cells. Several trophoblast cell lines have been derived from full-term placentae and these can be used to construct in vitro models of the placental barrier structure. Studies are currently underway to determine if cells in the full-term placentae of HIV-seropositive mothers are infected and which cell types are involved. At the most fundamental level, the mechanism by which HIV enters and/or traverses the trophoblast layer is not known. Chemokine receptor expression by trophoblasts and other placental cells is currently an area of intense investigation. Placentae of HIV-infected mothers have been found to express a different repertoire of cytokines and chemokines than seen in non-infected controls. Since chemokine receptors are now thought to be co-receptors for HIV entry this work has important implications for our understanding of maternal-fetal transmission. Ruptures in the placental barrier do occur, particularly during delivery, and it is important to understand more about what promotes or disturbs the stability of this barrier. Documented effects of ethanol in weakening cell adhesion could play a role in this context. Discontinuities in the trophoblastic layer in placenta occurring due to apoptosis have recently been described and this is another modification that has been linked to ethanol in other systems. Some questions that the investigator may seek to answer include: - Does alcohol affect the invasion of HIV across the placental barrier? - Can cellular models of this barrier be developed in vitro to test the impact of alcohol on membrane permeability and/or immunological functioning? - Can alcohol affect the immature immune systems of children of HIV-infected mothers? - Can an increase in viral strain diversity be seen in such children? - Does alcohol increase the risk of "trauma" to the membrane as a whole? - While alcohol is well known as a prenatal teratogen, can mechanisms of neuropathogenesis, as seen in fetal alcohol syndrome as well as HIV-dementia, be studied using in vitro models for barrier permeability? Technical considerations: Since primary or permanent cultures of endothelial cells that exhibit true BBB and PB characteristics are difficult to generate and maintain, applicants may consider the potential problems and solutions when developing comprehensive physical models for these barriers. Researchers may also wish to address some of the following topics in the course of their investigation: Maintaining brain microvascular endothelial cells - New sources and methods for isolating and maintaining BMVEC in a differentiated state - Use of BMVEC from gene modified or knockout animals - Characterization and quality control of BMVEC lines Culturing astrocytes and other co-cultivated cells lines - Sources and culturing methods for astrocyte and other BBB - Use of support cell lines from gene modified or knock out animals Performance of perfusion Devices - Commercially available hollow fiber bioreactors - Custom perfusion devices or chambers - Multiple or single fiber configurations - Pulsatile or peristaltic medium flow with variable shear stress parameters - Compatibility with confocal microscopy Performance of transwell Devices - Commercially available transwell Development of scaffolding materials and biocompatible substrates - Synthetic or biomaterial derived - Biodegradable - Extracellular matrix proteins, adhesion molecules, etc. Improvement of standardization and quality control - Time course for development and maintenance of EC barrier - Criteria for EC tight junction testing - High electrical resistance across EC barrier - Appropriate and selective transport of ions from the lumenal to the extracapillary compartments Comparison with in vivo models - Correlation of in vitro BBB and PB models with in vivo animal models - Internal carotid artery perfusion method - Injection and recovery method - Use of standard test compounds for transcellular and paracellular route of entry Application of analytical Techniques - Scanning electron microscopy - Transmission electron microscopy - Confocal microscopy - Immunocytochemistry and in situ hybridization - Permeability studies - Pharmacokinetic studies Special Concerns about Biohazards: The use of HIV and EC, monocytes and other cell types from HIV infected humans and/or animals mandates the strict adherence to laboratory safety standards and worker protection protocols. Annual meeting: Grantees are expected to meet annually to share results, to ensure that NIAAA has a comprehensive view of the technological advances in the field, to expedite the dissemination of new technology, and to afford an opportunity for collaborative problem solving among investigators. Applicants may request travel funds in their budgets for the principal investigator to attend these meetings. 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 are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. DATA AND SAFETY MONITORING PLAN As of the October 2000 receipt date, applicants must supply a general description of the Data and Safety Monitoring Plan for ALL clinical trials, this must be included in the application http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html The degree of monitoring should be commensurate with risk. NIH Policy for Data and Safety Monitoring requires establishment of formal Data and Safety Monitoring Boards for multi-site clinical trials involving interventions that entail potential risk to the participants. The absence of this information will negatively affect your priority score. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit 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 NIAAA staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: RFA-AA-02-008 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date indicated. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. 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. 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 also be sent to: RFA AA-02-008 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism Willco Bldg, Suite 409 6000 Executive Blvd, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the (IC). 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 NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and receive a second level review by the (IC) 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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 will scientific knowledge be advanced? 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 method? 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 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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 The adequacy of the proposed plan to share data, if appropriate. Schedule Letter of Intent Receipt Date: December 28, 2001 Application Receipt Date: January 23, 2002 Peer Review Date: March-April 2002 Council Review: May 2002 Earliest Anticipated Start Date: July 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Laurie Fleischman, Ph.D. Program Officer Collaborative and Special Health Programs Branch - CSHPB Office of Collaborative Research, NIAAA 6000 Executive Blvd, Room 302 Bethesda, MD 20892 Telephone: (301) 402-9402 FAX: (301) 480-2358 Email: lfleisch@mail.nih.gov Direct inquiries regarding fiscal matters to: Judy Simons Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2434 FAX: (301) 443-3891 Email: jsimons@niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 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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