DRUG DISCOVERY FOR THE TREATMENT OF ALZHEIMER"S DISEASE Release Date: January 8, 1999 PA NUMBER: PAS-99-034 (Reissued, see PAS-05-022) P.T. National Institute on Aging National Institute of Mental Health PURPOSE The National Institute on Aging (NIA) and the National Institute of Mental Health (NIMH) invite qualified researchers to submit research grant applications directed toward the discovery of novel compounds for the treatment of the cognitive impairment and behavioral symptoms associated with Alzheimer"s disease (AD). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000,"a PHS-led national activity for setting priority areas. This PA, Drug Discovery for the Treatment of Alzheimer"s Disease, is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325(telephone 202-512-1800) or at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic 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. Foreign institutions are not eligible for program project (P01) grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms of support for this Program announcement will be the National Institutes of Health (NIH) research project grant (R01) and program project grant (P01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed five years. FUNDS AVAILABLE At least $1.5 million will be committed by the NIA in FY 1999 and FY 2000 to fund applications of high scientific merit submitted in response to this Program Announcement. Although this program is provided for in the financial plans of the NIA and the NIMH, the award of grants pursuant to this PA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES I. BACKGROUND Alzheimer"s disease (AD) is one of the most persistent and devastating dementing disorders of old age, because it eventually leads to a complete loss of memory and of the ability to function independently. It is estimated that up to four million people in the United States have AD in its various stages at an estimated cost to society of $90 billion per year, and it is projected that 14 million people could be victims of Alzheimer"s disease by the middle of the next century. The disease presents enormous problems not only to affected individuals but also to their families and raises many complex social and economic issues for the country. AD provides a complex neurobiological puzzle. Its etiology is not known, and the pathobiological processes that underlie the steady progression of the clinical course of this disease are not yet completely understood. It is clear, however, that mechanisms of cell to cell communication are disrupted. These involve several different types of neurotransmitter, neuropeptide, and neuromodulator systems, neurochemical processes, protein trafficking, and elements of oxidative and cellular energy metabolism processes. The hallmark of the disease involves progressive cell dysfunction, cell loss, and the accumulation of a variety of abnormal protein and cytoskeletal abnormalities. At present it is still not known when and how the degenerative process begins, although a role in this process involving the amyloid precursor protein and amyloid beta protein as well as neurofibrillary pathology associated with the protein tau seems reasonable. At present there are no generally safe and effective treatments for the cognitive and behavioral symptoms of AD. The few agents that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the disease symptoms for relatively short periods in subsets of patients, and none has shown an effect on disease progression. The majority of the compounds considered candidate drugs have generally been designed to affect the synthesis, release, or degradation of neurotransmitters. Most of the agents available thus far have been targeted towards the cholinergic system which is an especially vulnerable neural population in AD and cognitive function. The NIA, NIMH and other NIH Institutes currently support extramural and intramural projects for the study of the epidemiology, etiology, diagnosis, and treatment of AD. Notwithstanding these efforts, the increasing numbers of affected individuals, the unknown etiology, the emotional, social, and economic costs to the victims, caregivers, and society, and the fact that there is no compound which can uniformly slow or reverse the progression of the disease or ameliorate the cognitive and behavioral symptoms, all require that the most creative scientific talents in all relevant scientific disciplines and organizations be mobilized to aggressively pursue a concerted effort to discover compounds and strategies for the treatment of the disease. Although agents are still needed which can ameliorate the symptoms of the disease even for a short time (because such agents would provide needed relief, however brief, to the victims and their families), new and novel efforts need to be focused on compounds which can slow the disease progression, reverse the disease process, and delay the onset of or prevent AD entirely. II. RESEARCH OBJECTIVES AND SCOPE The objective of this solicitation is to stimulate preclinical research in the discovery, design, development and testing of novel compounds aimed at slowing, halting, or, if possible, reversing the progressive decline in cognitive function and modifying the behavioral symptoms in Alzheimer"s disease victims as well as delaying the onset of or preventing AD. This initiative is intended to stimulate basic research and development efforts. The goal is not to duplicate or compete with pharmaceutical companies but to encourage, complement, and accelerate the process of discovering new, innovative, and effective treatments for cognitive impairment and behavioral symptoms in Alzheimer"s disease. The development of compounds for ameliorating, modifying, or improving potential aberrations in neuronal signal transduction pathways is encouraged. These treatments should be designed to affect fundamental processes of the neural dysfunction and cell death associated with the disease by targeting steps of the signal transduction pathway such as the cell membrane, second and third messengers, protein phosphorylation, and signal amplification stages including all facets of amyloid precursor protein, amyloid beta protein, and tau neurobiology, as well as energy utilization, oxidative mechanisms, and neurotrophin neurobiology. Research directed toward drug discovery utilizing one or more of the following examples or other novel approaches will be considered responsive to this PA. 1. Design and synthesis of compounds directed toward altering, modifying, or regulating the following aspects of signal transduction mechanisms: o Membrane and cytoskeletal composition, structure and function, o Protein phosphorylation and dephosphorylation, o Channel function and structure, o Second and/or third messengers, o Gene expression or transcription, o Neurotrophic and growth promoting factors, o Mitochondrial function and cellular energy metabolism, o Oxidative metabolism, o Synthesis, trafficking, and degradation of nervous system proteins including all facets of the neurobiology of amyloid precursor protein, amyloid beta protein, and tau, o Ionic transport. 2. The isolation, identification and characterization of promising naturally occurring products or synthetic chemical compounds. 3. Development of delivery systems to target compounds to the brain. The above-mentioned areas of investigations are representative and not meant to be inclusive. Investigators are encouraged to explore other avenues to identify potential therapeutic agents. Projects which include proposed animal model development or efficacy testing in animal models must integrate these areas within the major goal of targeted drug discovery. Large-scale random screening of compounds will not be supported under this PA, however, high-throughput screening of combinatorial chemical libraries may qualify for support. Extensive studies required for the clinical development of identified potential treatments, such as toxicological testing, are beyond the scope of this PA. 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 is provided 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, Number 11, March 18, 1994 available on the web at the following URL address: http://www.nih.gov/grants/guide/notice-files/not94-105.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may provide additional information concerning the policy. 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://www.nih.gov/grants/guide/notice-files/not98-024.html NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH Applications received in response to this program announcement are expected to focus on scientific issues related to aging and to aging-related aspects of disease. In describing the plan to recruit human subjects, investigators may cite a focus on aging or on aging-related aspects of disease as the justification for why children will be excluded. In this regard applicants may use Justification 1, the research topic to be studied is irrelevant to children, from the policy announcement. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://www.nih.gov/grants/funding/phs398/phs398.html The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html Submit the signed, original, single-sided application, along with five exact, single-sided copies and five collated sets of appendix materials 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. 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. o 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? o 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? o 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? o 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)? o 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? The initial review group will also examine: the appropriateness of proposed project budget and duration, the adequacy of plans to include both genders, children and minorities and their subgroups as appropriate for the scientific goals of the research, or the justification for their exclusion, plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Neil S. Buckholtz, Ph.D. National Institute on Aging Neuroscience and Neuropsychology of Aging Program Gateway Building 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: Buckholn@exmur.nia.nih.gov Linda S. Brady, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Room 11-97 Rockville, MD 20857 Telephone: (301) 443-9875 FAX: (301) 443-4822 Email: LB@helix.nih.gov Direct inquiries regarding fiscal matters to: Mr. Joseph Ellis National Institute on Aging Grants and Contracts Management Office 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: Joseph_Ellis@nih.gov Ms. Diana S. Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866 (NIA) and No. 93.242 (NIMH). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Note that there is a new publication of the NIH Grants Policy Statement published in the NIH Guide for Grants and Contracts on October 21, 1998 and available at http://www.nih.gov/grants/guide/notice-files/not98-146.html The PHS strongly encourages all grant and contract 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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