STUDIES OF SENSORY-MOTOR FUNCTIONS RESPONSIVE TO GRAVITY IN GENETICALLY ALTERED MODEL SYSTEMS Release Date: October 16, 2000 RFA: DC-01-001 National Institute on Deafness and Other Communication Disorders http://www.nidcd.nih.gov/ National Aeronautics and Space Administration http://www.nasa.gov/ National Institute on Aging http://www.nih.gov/nia/ Letter of Intent Receipt Date: December 18, 2000 Application Receipt Date: January 17, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This initiative seeks to stimulate research utilizing specific, well- characterized transgenic and mutant animal models to elucidate molecular bases for the normal development and function of sensory-motor mechanisms that detect and respond to gravity. Gravitational loading plays an important role in the development (maturation and aging) of the body’s gravity-sensing organs, notably the vestibular receptors, the proprioceptors, the central motor pathways and the skeletal muscles. These functions are fundamental to an organism’s ability to control its balance and posture, locomotion and other volitional movements, and its spatial orientation. A deeper understanding of the interactions between gravity and mechanisms of gene expression in sensory- motor functions would impact the fields of developmental biology, vestibular and motor physiology, space biology and space medicine. 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), Studies of Sensory-motor Functions Responsive to Gravity in Genetically Altered Model Systems, 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 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, subcontracts to foreign organizations are allowable, with sufficient justification. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Submission of an application in response to this RFA precludes concurrent submission of any other application containing substantially the same research proposal. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Exploratory/Developmental Grant (R21) award mechanism. This mechanism is utilized for pilot or feasibility studies to support exploratory research that may lead to innovative advances in the sciences. 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 RFA may not exceed three years. This RFA is a one-time solicitation. The anticipated award date is Aug 1, 2001. It is expected that feasibility/pilot data generated by these grants, if promising, will serve as a basis for a more extensive follow-up investigation, typically pursued through the submission of an R01 grant application. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The collaborating Agencies intend to commit approximately $1,000,000 Total Cost in Fiscal Year 2001 to fund up to six R21 grants in response to this RFA. An applicant may request a project period of up to three years and a budget for direct costs of up to $100,000 per year. These grants shall be administered according to NIH and grants policies and procedures. 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 NIDCD, NASA and NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background On June 21 and 22, 1999, the National Institute on Deafness and Other Communication Disorders (NIDCD) and the Life Sciences Division of the National Aeronautics and Space Administration (NASA) co-sponsored a program planning workshop, Role of Transgenic and Knockout Studies in Understanding Sensory- Motor Performance in Altered Gravitational Performance. A report of this workshop is available on the NIDCD Web site at http://www.nidcd.nih.gov/news/releases/99/june99.asp. This workshop explored the viability of studying the effects of altered gravitational exposure on sensory-motor function in genetically altered experimental model systems. Specifically, the workshop explored two interrelated questions concerning the use of genetically altered model systems. Can such models contribute to advancing our understanding of: 1) the development and function of sensory-motor mechanisms that detect and respond to gravity, and 2) the effects of altered gravitational exposure on such sensory-motor functions? Recent advances in molecular genetics have greatly enhanced the search for the genetic determinants of complex biobehavioral functions. The generation of mutant and transgenic animal models, involving such species as the mouse, Drosophila, zebrafish and Caenorhabditis elegans (C. elegans), provides powerful tools for elucidation of these functions. By illustration, a large number of zebrafish and mouse mutants with vestibular system involvement have been developed. Most have phenotypes with multiple defects and variable penetrance and expression. Notable exceptions are the tilted and tilted head mouse mutants, having only one identified phenotypic defect, the absence of otoconia, and 100% penetrance. The genetic bases for these mutants have not yet been established. By contrast, targeted deletion of genes such as Math1 (a mouse homolog of the Drosophila proneural gene atonal) or sequences encoding BRN 3.1 and BDNF produces congenital sensorineural anomalies of the inner ear. Although the existence of additional anomalies of the nervous system or other organ systems is difficult to exclude, the existing animal models are a valuable resource for understanding molecular bases for normal inner ear development. The expanded use of mutant and transgenic animals offers many promising tools for investigating molecular bases of balance function and sensory-motor performance. For example, the identification of regulatory sequences of genes expressed specifically in the vestibular system will allow the targeted introduction of foreign genes into the vestibular system of transgenic mice. These genetically-engineered animals could be designed to create specific animal models of human disease. In addition, such studies could facilitate targeted expression of potentially therapeutic genes to the vestibular system epithelium. The vestibular system is the primary sensor of angular and linear (including gravity) acceleration of the head. However, since all tissues in the body have mass, gravitoinertial acceleration also affects regional blood distribution, pulmonary function, movements of the abdominal viscera within the peritoneal cavity and both intraocular and intracranial pressure. Hence, sensory signals from these other organ systems also contain information about instantaneous linear and angular acceleration of the body. The sum of constant linear accelerations may be termed the gravitoinertial environment. Established chronic manipulations of effects of the gravitoinertial environment on different tissues include hypergravity, microgravity, exposure of fish embryos to simulated free-fall in a bioreactor and tail suspension/hindlimb unloading models in mammals. Since these manipulations affect multiple sensory systems, particular attention must be devoted to controls that discriminate vestibular from non-vestibular effects of exposure to altered gravitoinertial environments. Gravitational loading plays an important role in the development of the gravity-sensing organs, central motor pathways and both the structure and function of the skeletal muscles. Since the behavior of terrestrial animals has evolved under the static (1G) gravitational environment of earth, both the direction and magnitude of gravitational acceleration may be important implicit variables in molecular processes related to development, maturation and aging of the inner ear and of sensory-motor performance. The gravitational load also shapes the development and maturation of the extra-vestibular (e.g., proprioceptive) pathways that contribute to postural control. These pathways may play an important role in trophic interactions between motoneurons and muscle fibers. Alterations of the gravitational field cause widespread effects in many behaviors and physiologic domains. For example, recent studies have shown that chronic exposure to altered gravitoinertial environments can alter otolith morphology and vestibulo-ocular reflex performance in developing zebrafish. The neuromuscular system responds to altered gravitational load with shifts in expression of myosin isoforms and physiologic properties of muscle fibers. At the molecular level, exposure to microgravity (during space flight) can alter mRNA expression in a variety of adult mammalian tissues. A deeper understanding of interactions between gravity and mechanisms of gene expression would benefit the fields of developmental biology, space biology and space medicine. There is the need and opportunity to stimulate research utilizing specific, well-characterized transgenic ( knockout /null expression, knockin and conditional expression) and mutant animal models to elucidate molecular bases for the normal development and function of sensory-motor mechanisms that detect and respond to gravity. Appropriate animal models include C. elegans, Drosophila, Xenopus laevis, zebrafish and the mouse, although other relevant models may emerge. Scope This purpose of this RFA is to encourage the submission of applications for fundamental research that address at least one of the following goals: o Elucidate the molecular bases for functional development of sensory-motor mechanisms that detect and respond to gravitoinertial acceleration in a 1G environment, o Identify the molecular bases for functional maintenance and aging of normal sensory-motor function in a 1G environment, o Elucidate the influence of altered gravitoinertial environments on molecular bases for functional maintenance and aging of sensory-motor systems, and o Develop conditional knockout/knockin and transgenic models with restricted spatial and temporal gene activation programs that address these issues. Example of studies that address these goals include, but are not limited to: o Identification of the genetic bases for morphogenesis of the vestibular labyrinth, o Identification of the molecular bases for the development and maintenance of functional organization of sensory epithelia, including mechanisms regulating hair cell generation and normal establishment of the functional polarity of hair cells in the neuroepithelium, o Identification of the molecular bases for development of the afferent and efferent organization of vestibular neuroepithelia, o Identification of the molecular bases of and the influence of gravity on development of the cupulae and maculae in the inner ear, including a clarification of the role of gravity in the formation and maintenance of otoconia, o Identification of the effects of maturation of vestibular and extra- vestibular graviceptive pathways on trophic interactions between motoneurons and muscle fibers, o Identification of the molecular bases for development and maturation of sensory-motor pathways in the central nervous system that sense and respond to gravity, and o Characterization of the molecular mechanisms underlying altered performance of motor units and muscle fibers (e.g., atrophy and modified patterns of myosin expression) under altered gravitational conditions. 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 NIDCD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by December 18, 2000 to: Dr. Daniel Sklare Scientific Programs Branch Division of Extramural Research National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400C, MSC 7180 Bethesda, MD 20892-7180 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and 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. 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $100,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and their role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested (i.e., number of modules requested changes from one year to the next). o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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: Craig Jordan, Ph.D. Chief, Scientific Review Branch Division of Extramural Research National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400C, MSC 7180 Bethesda, MD 20892-7180 Applications must be received by January 17, 2001. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NIDCD. 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 NIDCD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may 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 National Deafness and Other Communication Disorders Advisory Council and the National Advisory Council on Aging. 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 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? 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. Schedule Letter of Intent Receipt Date: December 18, 2000 Application Receipt Date: January 17, 2001 Peer Review Date: March 2001 Council Review: May 24, 2001 Earliest Anticipated Start Date: August 1, 2001 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: Daniel A. Sklare, Ph.D. Scientific Programs Branch Division of Extramural Research National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400C, MSC 7180 6120 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-1804 FAX: (301) 402-6251 Email: daniel_sklare@nih.gov David L. Tomko, Ph.D. Biomedical Research and Countermeasures Program Life Sciences Division National Aeronautics and Space Administration Code UL, 300 E Street, SW Washington, DC 20546-0001 Telephone: (202) 358-2211 FAX: (301) 358-4168 Email: dtomko@hq.nasa.gov Judith A. Finkelstein, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: jf119k@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sherry Dabney Acting Chief, Grants Management Branch Division of Extramural Research National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400B, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: sd203o@nih.gov Mr. Lawrence P. Chambers Research Management Life Sciences Division National Aeronautics and Space Administration Code UL, 300 E Street, SW Washington, DC 20546-0001 Telephone: (202) 358-2196 FAX: (301) 358-4168 Email: lchamber@hq.nasa.gov Ms. Linda Whipp Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.173 and 93.866. 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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