CELLULAR REPAIR STUDIES OF THE AUDITORY AND VESTIBULAR SYSTEMS RELEASE DATE: June 6, 2002 RFA: DC-02-003 National Institute on Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) LETTER OF INTENT RECEIPT DATE: July 10, 2002 APPLICATION RECEIPT DATE: August 15, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) 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 National Institute on Deafness and Other Communication Disorders is committed to the treatment and elucidation of molecular mechanisms involved in human deafness and balance disorders. The primary cause of sensorineural hearing loss and impaired vestibular function results from damage and loss of auditory and vestibular sensory hair cells of the inner ear. Current clinical treatments are limited to the use of devices, hearing aids and cochlear implants, not the repair of the sensory cells. Irreparable loss of sensory hair cells can result from numerous factors including disease, aminoglycoside antibiotics, noise, and aging. In lower vertebrates hair cells are capable of regeneration following damage, but in mammals this capacity is absent. Recent advances in stem cell biology research, especially as related to tissue and cellular repair, hold great promise for the eventual treatment of hearing and balance disorders. The purpose of this RFA is to support fundamental stem cell biology research for repair, regeneration, and cell lineage delineation, as applied to the auditory and vestibular systems. RESEARCH OBJECTIVES The auditory and vestibular neuroepithelia are critical to the functional processes of hearing and balance. The hair cells residing in the cochlea are responsible for sound transduction, and the hair cells of the semicircular canals and otholithic organs are responsible for sensing rotational and linear acceleration forces of the head. The loss of these hair cells in mammals leads to the irreparable loss of hearing and vestibular mediated balance function. Two contributing research avenues that could impact cellular restoration of hearing and balance function are hair cell regeneration and development. Regenerative studies have consisted primarily of comparative analyses between the regenerative ability of avian systems versus the lack of regenerative ability in mammals. Avian hair cell regeneration involves the up-regulation of cell proliferation and differentiation of postmitotic cells, whereas mammalian auditory and vestibular organs show little evidence of terminal hair cell differentiation from postmitotic cells. These renewing processes in the avian system result in repopulation of hair cells and full restoration of hearing and balance function. While understanding the biological processes of avian renewal is important, there is insufficient data to determine the clinical value to humans. Auditory and vestibular developmental studies have revealed an exceptionally elegant and complex system. The eventual formation of the inner ear involves the convergence and contribution of the epithelium, mesenchymal, mesodermal and neural crest cell layers. Specifically, the invagination of the placodal ectoderm leads to the formation of the otic placode, eventually giving rise to a defined base of auditory and vestibular sensory hair cells and non-sensory support cells. This process occurs early in embryonic development and once a full complement of hair and support cells is established, division of the precursor cells cease. Elucidation of the putative progenitors and the molecular factors that impact these differentiation and regenerative events will be crucial to defining cell lineage in the auditory and vestibular organs. The self-renewal and plasticity characteristics intrinsic to the stem cell hold the promise of significant clinical application, and stem cell research in regenerative and reparative therapy provides new avenues of auditory and vestibular research exploration. To date, stem cell populations have been identified from almost all normal tissues including mesenchymal, peripheral and cord blood, neuronal and muscle, and offer numerous possibilities for putative regenerative capabilities. Knowledge acquired from these other systems may be biologically relevant to the auditory and vestibular systems. Similarly, research information acquired from the auditory and vestibular environment may have reparative relevance for other tissue and organ systems. At the core, many fundamental questions exist: factors determining a cell"s multipotency that allow replenishing capabilities, mechanisms and factors regulating de-differentiation and trans-differentiation into a multipotent cell, factors and molecules involved in the interaction and integration of a newly transplanted cell and the microenvironment. Eventually, these questions should be addressed for every tissue type and organ system to realize the full potential of stem cell biology therapy. Objectives and Scope The potential translational application of stem cell biology research to the auditory and vestibular systems is the focus of this initiative. Research efforts on the cellular, molecular and genetic mechanisms that influence the lineage choices of stem cells relevant to the auditory and vestibular systems are of high importance. Research areas of great interest include, but are not limited to: o Identification of auditory and vestibular progenitor cells. It is unclear if stem cells exist in the auditory and vestibular systems, and if hair cell generation involves "reserve" stem cells or dedifferentiation of other cells. The putative replenishing involvement of support cells in the generation of hair cells is also unknown. Identification studies of true stem cell progenitors versus products of trans-amplification are needed. o Identification of auditory and vestibular cell specific markers. In vivo and in vitro integration studies will require input cell validation, and should assess clonality. Identification of cell specific receptors, surface antigens etc., are needed. o Development and validation of physiological assays. Cells delivered to a test environment will have to demonstrate function that is critical for experimental validation. Development of assays that permit accurate and reliable characterization of integrated stem or precursor cells in the auditory and vestibular systems is needed. o Development of cell purification and expansion technologies. Ultimate use and therapeutic efficacy will be dependent upon the validation of cell source. The auditory and vestibular organs, due to small size and limited accessibility, pose a difficult challenge to cell harvest and purification. Development of novel technologies and methodologies to isolate and expand pure lines of putative progenitors are needed. o Cellular and molecular commonalities. It is unknown if stem cells from other sources can be stimulated to differentiate into auditory and/or vestibular cells. Stem cells harvested from various sources are currently being used successfully in other reparative systems and their use to replenish the auditory or vestibular systems should be investigated. o Auditory and vestibular microenvironment. There is a need to elucidate developmental and signaling pathways to identify combinatorial effects between putative progenitor cell markers and the surrounding cellular environment. There is a need to identify agents, such as morphogens, feeder lines, and growth conditions that would allow propagation of auditory and vestibular progenitors in vivo or in vitro specifically for reparative assays. o Vector and delivery systems. Synthetically fabricated or biologically based support platforms are needed to allow propagation, delivery and integration of cell populations within the auditory and vestibular systems. The development of new and novel surgical approaches to deliver these systems into auditory and vestibular target environments is needed. o Transplantation studies. Feasibility studies are needed to explore cellular replacement within the auditory and vestibular systems. Identification and characterization of putative target areas for both hair cell regeneration and neural restoration is needed. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R21 EXPLORATORY/DEVELOPMENTAL GRANT) and R01 (INVESTIGATOR INITIATED RESEARCH GRANT) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA will have one submission date: August 15, 2002. Beyond this date, future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is April, 2003. Investigators may submit more than one application for this RFA. Generally, applications proposing exploratory/feasibility studies with limited preliminary data should use the R21 mechanism, while applicants proposing more extensive projects based on significant published and preliminary results should use the RO1 mechanism. In addition, applicants are strongly encouraged to contact the scientific Program Officer listed below under INQUIRIES to discuss which mechanisms (R21 or RO1) would be most suitable for the proposed research project. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (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. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The NIDCD intends to commit approximately $1,500,000 in FY 2003 to fund up to 3 to 5 new R21 and 3 to 5 new R01 grants in response to this RFA. Because of the exploratory nature of the R21, applicants submitting an R21 may only request a budget for direct costs of up to $100,000 per year for a maximum of two (2) years. R01 applicants may request a project period of up to five (5) years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIDCD 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. 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 Applications in response to this RFA with the intent to use human embryonic stem cells (hESC) must comply with federal guidelines. A cover letter signed by the principal investigator, appropriate institutional official and business office, acknowledging review and approval of the grant application proposing human embryonic stem cell research must be included. All applications must indicate the official identifier(s) for the appropriate hESC line(s) as found in the NIH Registry (http://escr.nih.gov/). In addition, compliance to all of the federal guidelines must be satisfied. These NIH guidelines are listed at, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-049.html. Applications not including this information will be returned without further consideration. Answers to frequently asked questions about hESC may be found at: https://grants.nih.gov/grants/stem_cell_faqs.htm This announcement highly encourages collaboration between stem cell biologists and auditory/vestibular investigators. 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: o Direct your questions about SCIENTIFIC/research issues to: Dr. Nancy L. Freeman Scientific Program Director National Institutes of Health National Institute on Deafness and Other Communication Disorders Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Bethesda, MD 20892-7180 nancy_freeman@nih.gov Tel: (301) 402-3458 Fax: (301) 402-6251 o Direct your questions about peer REVIEW issues to: Dr. Craig Jordan Chief, Scientific Review Branch Division of Extramural Research National Institutes of Health National Institute on Deafness and Other Communication Disorders Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Bethesda, MD 20892-7180 Telephone: 301-402-8683 Fax: 301-402-6250 Email: jordanc@nih.gov o Direct inquires of FINANCIAL or grants management matters to: Ms. Sara Stone Chief, Grants Management Branch Division of Extramural Research National Institutes of Health National Institute on Deafness and Other Communication Disorders Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 Fax: (301) 402-1758 Email: stones@nidcd.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 institute staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by July 10, 2002. The letter of intent should be sent to: Dr. Nancy L. Freeman Scientific Program Director National Institutes of Health National Institute on Deafness and Other Communication Disorders Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Bethesda, MD 20892-7180 nancy_freeman@nih.gov Tel: (301) 402-3458 Fax: (301) 402-6251 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. ADDITIONAL R21 APPLICATION PROCEDURES All application instructions in the PHS 398 research grant application instructions and forms (rev. 5/2001) apply to the R21 with the exception of the following modifications: 1. R21 applications may request up to four (4) $25,000 modules for a maximum direct cost of $100,000 per year for up to a maximum of two (2) years. 2. The Research Plan for the R21 application may not exceed 10 pages. Tables and Figures (color and black and white) must be included within the 10-page limit. However, to aid reviewers, additional original color figures should be included in the appendices if the data cannot be adequately evaluated when copied in black and white (see APPLICATION SUBMISSION.) 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 and appendix material must be sent to: CHIEF, SCIENTIFIC REVIEW BRANCH DIVISION OF EXTRAMURAL RESEARCH NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS 6120 EXECUTIVE BOULEVARD, ROOM 400-C, MSC 7180 BETHESDA, MD 20892-7180 ROCKVILLE, MD 20852 (for express/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 NIDCD. Incomplete and non-responsive applications will be returned 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: 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 and assigned a priority score o Receive a second level review by the NDCD Advisory 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 your 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 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, 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 DATA SHARING: The adequacy of the proposed plan to share data. o OTHER REVIEW CRITERIA: RO1/R21 applications proposing the use of human embryonic stem cells will not be required to contain the same amount of pilot data as judged for a typical RO1/R21. It is appreciated that this area of investigation is in the early stages of research development and assessment of pilot data will be reviewed accordingly, however, the application still must demonstrate the feasibility of the approach. 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: July 10, 2002 Application Receipt Date: August 15, 2002 Peer Review Date: November, 2002 Council Review: January 2003 Earliest Anticipated Start Date: April 1, 2003 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 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. 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. 93.173 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.

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