PA-04-154: HIV INFECTION OF THE CENTRAL NERVOUS SYSTEM

Department of Health
and Human Services (HHS)

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HIV INFECTION OF THE CENTRAL NERVOUS SYSTEM RELEASE DATE: September 2, 2004 PA NUMBER: PA-04-154 November 22, 2006 - The R01 portion of this funding opportunity has been replaced by PA-07-089, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond.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. This announcement will stay active for only the May 1, 2006 AIDS and AIDS-related application submission date for these mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 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. Parent R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates for AIDS and non-AIDS applications thereafter. Applications relating to R33 and R34 activities must be in response to NIH Institute/Center (IC)-specific announcements. EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006 EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 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 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) National Institute of Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.242 (NIMH), 93.853 (NINDS), 93.279 (NIDA), 93.273 (NIAAA) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support 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 This PA replaces PA-01-072. The National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Drug Abuse (NIDA), and National Institute of Alcohol Abuse and Alcoholism (NIAAA) invite research grant applications through this Program Announcement (PA) to support research focused on determining the pathogenic mechanisms involved in Human Immunodeficiency Virus (HIV)-1 associated neurobehavioral and neurological dysfunction in domestic and international settings. The objective of this cooperative effort is to foster investigations that will provide the foundation for the rapid development of therapeutic interventions to prevent and treat the effects of HIV-1 on the central nervous system (CNS). Applications ranging from basic research to clinical diagnosis and treatment are of interest. Multidisciplinary research teams and collaborative alliances are encouraged but not required. RESEARCH OBJECTIVES The introduction of highly active anti-retroviral therapy (HAART) has resulted in significantly improved survival of AIDS patients and decreased incidence of HIV- associated dementia (HAD). HAD is estimated to constitute about 5% of new AIDS- defining illnesses in the USA. Despite the reduced incidence of HIV dementia, the improved survival has resulted in increased cumulative prevalence of nervous system complications of AIDS. HAART does not provide full protection against neurological damage in HIV/AIDS in part, because the blood-brain barrier is only partially permeable to anti-retroviral agents. The frequency of HIV-associated encephalitis observed in post-mortem tissue has remained constant, suggesting that HAART does not eliminate HIV-1 infection in the central nervous system. Furthermore, while improvements in treatment for AIDS have occurred in the developed world, a significant number of new infections are being reported in the developing countries including China, India, Eastern Europe, and Sub-Saharan Africa. The neurologic and neuropsychiatric complications resulting from new infections in the developing world are likely to cause significant morbidity and mortality. Extensive research is underway to better understand the underlying mechanisms of neuropathogenesis of HIV-1. Currently there is limited consensus on the pathways leading to neurologic and neuropsychiatric disease in the setting of HAART. While HAART has resulted in increased prevalence of HIV dementia, the neurologic disease has been reported to be milder. It has been suggested that in the era of HAART, distinct subtypes of HAD are observed. The proposed subtypes include the following: a) subacute progressive dementia; b) chronic active dementia; and c) chronic inactive dementia. The research efforts over the last two decades have resulted in an improved understanding of the pathophysiology of HIV-induced nervous system disease. However, many fundamental gaps remain in our knowledge relating to mechanisms and pathways involved in the development of HIV-associated neurologic and neuropsychiatric disease. An important emerging area of research interest is the exploding HIV epidemic in resource-poor settings and the impact on nervous system disease. There is an urgent need for research on the epidemiology and natural history of neurologic and neuropsychiatric disease in the affected regions of the world. Another critical research need relates to studies of mechanisms by which distinct viral clades impact on HIV-neuropathogenesis and associated co-infections and opportunistic infections in resource-poor settings. In an effort to intensify the depth, focus, and coordination of key neuro-AIDS issues, NIMH, NINDS, NIDA, and NIAAA are jointly issuing this Program Announcement. The following are examples of research areas that are pertinent to this PA add examples only, not limited to these topics: Primary and Secondary Mechanisms of HIV-1 Neuropathogenesis o Mechanisms of entry of cell-associated and cell-free virus into the CNS compartment through the blood-brain barrier. Role of cytokines, chemokines, chemokine receptors, adhesion molecules and syndecans in facilitating HIV trafficking into the CNS. o Mechanisms of infection and productive replication of HIV in cells derived from the CNS compartment including microglia, macrophages and astrocytes. o Interactions of viral proteins (Tat, Vpr, Nef, gp 120) with CNS derived cells. These include studies of the impact of viral proteins on damage to blood-brain barrier, induction of release of mediators (chemokines, cytokines, excitotoxins) and activation of apoptotic pathways, particularly in neuronal cells. o Roles of excitotoxicity and the production of reactive oxygen species as mechanisms of neuropathogenesis in HIV-1 infection of the CNS. o Impact of host derived mediators and associated receptors (cytokines, chemokines, chemokine receptors, matrix metalloproteinases, thrombin, proteinase- activated receptors)on HIV-neuropathogenesis. o Signaling pathways involved in neuronal damage and apoptosis or release of inflammatory mediators following interaction of virus or viral proteins with CNS- derived cells. o Role of adaptive and innate immunity in regulating anti-viral responses in the CNS compartment. o Cellular and viral factors that maintain viral latency or promote viral activation and recrudescence in the brain. o Roles of pharmacomodulation of cytokine/chemokine receptor activity and related mechanisms of neuropathogenesis in HIV-1 infection of the CNS. o Neural-glial interactions focusing on interrelated cytokine/chemokine systems and the modulation by endogenous opiate/cannabinoid systems. o The ability of chronic alcohol intake to facilitate the entry of HIV-1 to the nervous system through the blood-brain barrier, and to augment the development and progression of HAD via potentiating HIV-induced neurotoxicity or excitotoxicity, activating apoptotic or other signal transduction pathways, or further compromising immune function. o Early morphologic or metabolic alterations that may precede or be associated with onset of cognitive impairment in HIV-positive individuals with confounding disease state/drug dependence. Viral and Host Genetics o Viral Evolution in the CNS. a. The role of viral evolution and trafficking in establishing regional genetic heterogeneity of HIV-1 in CNS. b. Comparisons of sequences of HIV strains derived from CNS and other organs for assessment of compartmentalized virus evolution. o HIV-1 Molecular Diversity and Resulting Functional Consequences. a. Molecular diversity of various HIV-1 genes (e.g., Tat, Nef, Vpr) 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. The role of HIV-1 envelope protein in inducing neurotoxicity and 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. 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. o Emergence of Drug Resistance in CNS parenchyma/CSF versus other body compartments. a. 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. o Host genetic factors and markers linked with susceptibility and progression of HIV-associated nervous system disease. o Pharmacogenomic studies to identify genetic markers and polymorphisms linked with host response to anti-retroviral therapy. For example, polymorphisms in the mdr gene are associated with differences in protease inhibitor levels and magnitude of CD4+ count recovery under therapy. Molecular Markers Associated with HIV-Induced Nervous System Disease o Microarray analysis of HIV-infected human CNS tissue or animal models of neuroAIDS at various stages of disease progression to identify modulation of unique genes. Genes of interest can be further characterized to delineate their molecular identity as well as their functional role in neuropathogenesis. o Use of proteomics to uncover protein signatures associated with HIV infection in various peripheral and CNS cell populations and biological fluids of patients at various stages of disease progression. Protein chip technologies may be utilized to identify unique protein profiles associated with neurological and neuropsychiatric manifestations of HIV infection. Neuroimaging Studies o Use of neuroimaging approaches such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET), magnetic resonance imaging (MRI), functional MRI (fMRI), blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) and diffusion tensor imaging (DTI)to delineate key biological markers that correlate with disease symptoms and progression. Neuroimaging studies are also useful in establishing relationships between spectroscopic markers and histopathologic markers of neuronal health and inflammation. Studies of the role of unique inflammation-related markers identified by neuroimaging, in the pathophysiology of neuroAIDS, are relevant. o Unique issues associated with actions in IV drug abusers, especially focusing on regions or circuits relevant to drug abuse (e.g., mesocortical limbic system, hippocampus, frontal cortical areas, pyramidal and extrapyramidal motor areas). Studies on children and youth are encouraged. o Improved statistical and innovative neuroimaging methods for drug abuse. HIV/Hepatitis C(HCV)Co-Infection and Opportunistic Infections of the CNS o The prevalence, qualitative and quantitative features of HCV induced neurocognitive impairment in the setting of co-infection with HIV. o Mechanisms of HCV-induced neurocognitive impairment including host and viral factors and their interactions. o Interactions between HIV-1 infection, immunodeficiency and the spread of other infectious agents in the CNS. Therapeutics o Developing HIV-1 therapeutic agents capable of penetrating the blood-brain barrier (alternate approaches may include manipulation of efflux transporters, such as P-glycoproteins, to improve access of anti-HIV agents across the BBB). o Adjunctive therapies including neuroprotective strategies to treat HIV-induced nervous system disease. NeuroAIDS Research in Resource-limited Settings o The incidence and prevalence of neurological and neuropsychiatric disease caused by HIV and associated opportunistic infections (toxoplasmosis, cryptococcal meningitis) and co-infections (hepatitis C, cerebral malaria) in the presence/absence of drug or alcohol abuse. o Molecular analysis of clades prevalent in resource-limited settings and studies of mechanisms of neuropathogenesis caused by non-subtype B viruses. o Impact of host-genetic factors in regulating susceptibility to nervous system disease caused by HIV and associated opportunistic infections and co-infections. The use of animal models (non-human primates, transgenic mice/rats) is encouraged. Studies of HIV-1 infection of the brain have been slowed by the lack of well characterized human CNS tissues. Such tissue samples (brain, spinal cord, cerebral spinal fluid, blood, lymphocytes) are currently available from the National NeuroAIDS Tissue Consortium (http://spitfire.emmes.com/study/hbb/), which can be used as a resource for these studies. MECHANISM(S) OF SUPPORT This PA will use the NIH research project grant (R01) and exploratory/developmental grant (R21) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. 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 a 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 to $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 PA uses just-in-time concepts. It also uses the modular budgeting 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 budget format. Otherwise follow the instructions for non-modular budget 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_2003/NIHGPS_Part2.htm. 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 PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Jeymohan Joseph, Ph.D. Chief, HIV Neurovirology, Genetics and Molecular Therapeutics Program Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6202 Bethesda, MD 20892 Telephone: (301) 443-3012 FAX: (301) 443-9719 Email: jjeymoha@mail.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) 594-6034 Email: cs107m@nih.gov Michael Nunn, Ph.D. Neural Environment Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2118 Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: mn52e@nih.gov Roger Sorensen, Ph.D., M.P.A. Division of Neuroscience and Behavior National Institute on Alcohol Abuse and Alcoholism 5635 Fishers Lane, Room 2058, MSC 9304 Bethesda, MD 20892-9304 Telephone: (301) 443-2678 FAX: (301) 443-1650 Email: rsorense@mail.nih.gov o Direct your questions about financial or grants management matters to: Mr. Brian Albertini Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115 Bethesda, MD 20892 Telephone: (301) 443-0004 FAX: (301) 443-0219 Email: albertib2@mail.nih.gov Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse/NIH/DHHS 6101 Executive Boulevard, Suite 270, MSC 8403 Bethesda, MD 20892-8403 Telephone: (301) 443-6710 FAX: (301) 594-6849 Email: gf6s@nih.gov James Washington, M.Ed. Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3254 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: washingj@ninds.nih.gov Judy S. Fox Chief Grants Management Officer National Institute of Alcohol Abuse And Alcoholism 5635 Fishers Lane, Room 3021, MSC 9304 Bethesda, MD 20892-9304 Telephone: (301) 443-9704 FAX: (301) 443-4704 Email: jfox@mail.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 D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B 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) 710-0267, 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. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget grant format. The modular budget 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 $500,000 or more 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 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 unfunded version 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. Appropriate scientific review groups 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 evaluate 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 the following criteria in assigning the 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. 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? 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? 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? 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)? 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 $500,000 or more 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 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 ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. 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: 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. 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. 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 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. 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). 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 PA 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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