NEURODEGENERATIVE DISEASE ASSAYS FOR HIGH THROUGHPUT DRUG SCREENING AND CHEMICAL GENETICS RELEASE DATE: January 22, 2002 RFA: RFA-NS-02-012 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Institute of Neurological Disorders and Stroke, NINDS (http://www.ninds.nih.gov/) LETTER OF INTENT RECEIPT DATE: February 26, 2002 APPLICATION RECEIPT DATE: March 26, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Special Requirements 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 purpose of this RFA is to encourage the use of high throughput drug screening and chemical genetics in Neurodegeneration research by funding the development of assays that may be adapted for high throughput approaches. RESEARCH OBJECTIVES Background Recent advances in the study of neurodegenerative disease have provided molecular and cellular models for studying the underlying disease mechanisms. Many of the same models can be adapted for use in automated drug screening efforts. Drug screening is a potentially powerful approach to further elucidate disease mechanisms and to identify new treatments. An effective strategy developed by the pharmaceutical industry to identify new drugs is high throughput drug screening (HTS), using robotics to simultaneously test thousands of distinct chemical compounds in miniaturized versions of disease models. HTS is also being applied in a basic research strategy, known as chemical genetics, to identify new components of disease causing pathways. Chemical compounds that inhibit or activate specific proteins are useful in ways that are analogous to true genetic mutations. In the same way that an inactivating mutation can uncover the role of a new molecule in a disease process, a chemical compound that inhibits the function of that molecule can be used to get information about its identity, its activity and its interacting partners. Many of the in vitro disease models currently used to study the effects of specific compounds or genetic influences can be adapted to high throughput formats. There are a number of characteristics that make an assay suitable for high throughput approaches. For example, it must be possible to reduce the assay to a 96-well format. The assay must be robust, reproducible, and have a simple readout. Many different kinds of assays have these features, including biochemical processes, cell-based models or simple model organisms such as yeast or C. elegans. This RFA is intended to encourage the design and development of in vitro assays for neurodegeneration that may subsequently be adapted for high throughput approaches. This RFA is one component of a program to stimulate the use of chemical genetics and high throughput drug screening in neurodegeneration research. Drug screens will be supported through an NINDS contract for a centralized high throughput screening facility that is scheduled for award in 2002. A synopsis of this request for proposals may be found at https://grants.nih.gov/grants/guide/notice-files/NOT-NS-02-004.html. Personnel at this facility will work collaboratively with outside investigators to adapt neurodegeneration assays for HTS, and then use these assays to screen a large, diverse compound collection. The current RFA is intended to encourage the development of assays to be screened at the facility. Because the facility will adapt the assays for HTS if necessary, experiments proposed in response to this RFA need not include the use of assays in high throughput screens or even the final stages of miniaturization for HTS. Rather, the emphasis is on designing and validating creative approaches to assaying neurodegeneration that can potentially be used for chemical genetics and drug discovery. Scope Assays proposed for this initiative should represent mechanisms associated with neurodegenerative diseases, including Parkinson's Disease, Amyotrophic Lateral Sclerosis, Alzheimer's Disease and triplet repeat disorders such as Huntington's Disease. Assays may involve proteins, cells or model organisms. However, it should be feasible to use the assay in an automated, high throughput screening approach. To allow maximum flexibility in the kinds of assays tested at the NINDS HTS facility, the facility will have the capacity to screen assays in what is considered moderate throughput by current industry criteria. Assays that cannot be scaled below the 96-well format will be acceptable for screening at the NINDS facility. Thus, an assay need not be adaptable to ultra high throughput format to be appropriate for this announcement. Appropriate assays include: o Toxicity of disease-causing proteins in neuronal cell lines or primary neuronal cultures. o Toxicity of disease-causing proteins in yeast or other model organisms. o Modulation of expression of disease-causing or neuroprotective genes, including effects on transcription, translation or splicing. o Cell-based assays of activity, processing or turnover of disease-causing or neuroprotective proteins. o Biochemical assays of activity of disease-causing or neuroprotective proteins. Because protein aggregation is already an active area for assay development, aggregation assays are not strongly encouraged unless the proposal includes a novel element, such as demonstration of a causal relationship between the state of aggregation and pathogenesis. Proposals should include plans to develop and validate an assay to the point where it appears feasible to adapt the assay for automated screening through further collaboration with the NINDS or another HTS facility. Demonstration of feasibility for eventual HTS may include: o Demonstration of highly predictable and reproducible response to pharmacological standards. o Demonstrated selectivity and reproducibility of response to a small but diverse collection of compounds, such as a collection of FDA approved drugs. o The availability of reliable secondary screens to evaluate the significance of compounds identified in the primary high throughput assay. Use of the assay for high throughput screening need not be an aim of the proposal, but as discussed in the SPECIAL REQUIREMENTS section below, plans for screening the assay and validating the results of the screen should be described. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R21 award mechanism. Specific modifications to the application instructions, detailed below, reflect the nature of this mechanism and the purpose of this RFA. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The total project period for an application submitted in response to this RFA may not exceed 2 years. This RFA is a one- time solicitation. Competitive renewals of grants awarded under this RFA will not be accepted. The earliest anticipated award date is September 30, 2002. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://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 NINDS intends to commit approximately $1.5 million in FY 2002 to fund 7 to 10 new grants in response to this RFA. An applicant may request a project period of up to 2 years and a budget for direct costs of up to $125,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NINDS provides 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. At this time, it is not known if this RFA will be reissued. 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. SPECIAL REQUIREMENTS Because the ultimate goal for assays developed under this RFA is HTS, investigators should describe their goals relevant to HTS. This should include a discussion of the goals and expected outcome of a chemical genetic screen or drug screen for which the assay is designed. In addition, the investigator should indicate their interest in having their assays adapted for screening at the NINDS HTS facility, or present a feasible alternative plan for using the assay in HTS. 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: Direct your questions about scientific/research issues to: Dr. Jill Heemskerk Program Director, Technology Development National Institute of Neurological Disorders and Stroke NSC, Room 2229 6001 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (For express or courier service) Telephone: (301) 496-5680 FAX: (301) 480-1080 Email: jill_Heemskerk@nih.gov Direct your questions about peer review issues to: Dr. Lillian Pubols Chief, Scientific Review Branch, NINDS Neuroscience Center, Suite 3208, MSC9529 6001 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (For express or courier service) Telephone: (301) 496-9223 Email: PubolsL@ninds.nih.gov Direct your questions about financial or grants management matters to: Ms. Chris Davis Grants Management Specialist Grants Management Branch, DER, NINDS Neuroscience Center, Room 3271 6001 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (For express or courier service) Telephone: (301) 496-7386 FAX: (301) 402-0219 Email: DavisC@ninds.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 February 26, 2002, to Dr. Jill Heemskerk at the address above. This letter may be sent by email. 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 https://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. SUPPLEMENTAL INSTRUCTIONS: Use the revised version of form PHS 398 with the following modifications: o Research Plan: The research plan may not exceed 15 pages. No appendices are permitted. o Item a, SPECIFIC AIMS: The instructions for this section suggest that the applicant state "the hypotheses to be tested." Hypothesis testing per se may not be the driving force in developing proposals for this RFA and, therefore, may not be applicable. Thus, the applicant should state the hypothesis, design and/or need which will drive the proposed research. o Item b, BACKGROUND AND SIGNIFICANCE: In this section it is important to clearly elaborate the rationale for the proposed assay and its intended purpose, e.g., drug screening or chemical genetics. o Item c, PRELIMINARY DATA: There is no requirement to generate preliminary data for these applications. However, the application should make clear that the proposed assay is scientifically sound, and any available preliminary data should be presented. o Item d, RESEARCH DESIGN AND METHODS: It is important to present long range plans for evaluating the significance of chemical leads resulting from future screening of the proposed assay. These may include descriptions of secondary in vitro screens and testing in animal models. 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 https://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 https://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: https://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: Dr. Lillian Pubols Chief, Scientific Review Branch, NINDS Neuroscience Center, Suite 3208, MSC 9529 6001 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (For Express or Courier Service) 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 NINDS. 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 NINDS 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, assigned a priority score o Receive a second level review by the National Advisory Neurological Disorders and Stroke Council. 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: o Significance o Approach o Innovation o Investigator o Environment o Feasibility for HTS o Future Plans 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 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 methods? 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? (6) FEASIBILITY FOR HTS: Although high throughput screening is outside the immediate scope of this announcement, is it feasible to adapt the assay to a high throughput format? Is it likely that the assay will produce reliable results in a high throughput screen? (7) FUTURE PLANS: For future use of the assay, has a facility been identified that can adapt and screen the assay in a high throughput format? Is there an adequate plan for evaluating the activities of compounds identified in a high throughput screen, e.g., in secondary screens? Are there important and well- defined goals for the use of active compounds identified using this assay, either for drug discovery or for use as research tools? 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 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: February 26, 2002 Application Receipt Date: March 26, 2002 Peer Review Date: June/July 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 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 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://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 https://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 No. 93.853, 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 https://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. https://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.
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