RFA-DC-04-003: PROTEIN INTERACTIONS IN AUDITORY AND VESTIBULAR BIOLOGY

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.

PROTEIN INTERACTIONS IN AUDITORY AND VESTIBULAR BIOLOGY RELEASE DATE: June 21, 2004 RFA Number: RFA-DC-04-003 EXPIRATION DATE: October 23, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.173 LETTER OF INTENT RECEIPT DATE: September 24, 2004 APPLICATION RECEIPT DATE: October 22, 2004 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 Supplementary Instructions 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 (NIDCD) invites applications to study protein interactions involved in auditory and vestibular development. Previous decades using molecular biology approaches have provided a wealth of molecular tools to dissect complex protein interactions involved with numerous molecular pathways. While advances in gene identification and regulation have been made in the auditory/vestibular systems, understanding how the complex orchestration of specific signaling events translates to protein function remains elusive. The availability of molecular technologies that allow specific protein targeting and tagging to address function provides new opportunities for protein analysis in auditory and vestibular function. The purpose of this RFA is to initiate multi- faceted approaches to understand protein function important in auditory and vestibular biology. RESEARCH OBJECTIVES The complex development of auditory and vestibular organs and their mechanosensory hair cells involves numerous genes and proteins as the molecular drivers for hearing and balance function. Detailed events spanning otic placode development have profited from gene and phenotypic characterization in powerful model systems such as mouse, chick, and zebrafish. While critically valuable, analyzing targeted genetic mutants and mutagenized screens can take several years of characterization before forward approaches of interactive protein work can be initiated. Numerous transcription factors and signaling molecules participating in otic and vestibular morphogenesis have been identified, but a critical gap remains in molecular studies that explore the interactive dynamics of these regulatory and signaling molecules. Protein studies, both in vitro and in vivo, have provided comprehensive approaches to identify critical binding partners, domain interactions, amino acid mutational effects, and functional oligomerization and phosphorylation processes. These approaches typically encompass both binding and cellular protein localization assays, and allow direct assessment of individual protein (and domain) interactions with putative or unidentified interactive partners, associations which provide the connective atlas of cellular function. Studies commonly involve the use of antibodies, and/or combination of both prokaryotic and eukaryotic recombinant protein fusion expression systems such as glutathione-S-transferase (GST), polyhistidine tags, Flag ocatapeptides, and green fluorescent protein (GFP), which can facilitate purified reconstitution assays, as well as resolution of protein crystal structure. Even with the onset of powerful high throughput proteomics/genomics approaches, the resulting identification of protein regulatory networks will require validation using some aspect of these approaches. The goal of this RFA is to initiate comprehensive approaches using multiple molecular techniques to study regulatory and signaling proteins important in auditory and vestibular developmental biology. Information gained from these approaches will provide insight to specific protein regulatory networks important to auditory and vestibular function. Applications using high-throughput proteomics approaches are not considered responsive and should apply under PA: PROTEOMICS IN AUDITORY DEVELOPMENTAL AND DISEASE PROCESSES (http://grants.nih.gov/grants/guide/pa-files/PA-03-151.html). In addition, applications performing microbial/pathogen investigations are not considered responsive and are directed to consider the appropriateness of PA: RESEARCH ON MICROBIAL BIOFILMS (http://grants.nih.gov/grants/guide/pa-files/PA-03-047.html), or PA: NOVEL APPROACHES TO STUDY POLYMICROBIAL DISEASES (http://grants.nih.gov/grants/guide/pa-files/PA-04-093.html). It is anticipated that various combinations of the following examples would be proposed. Studies to be funded in response to this RFA could include, but are not limited to: o Use of auditory/vestibular protein(s) in bacterial or yeast two- hybrid systems to detect putative protein interactions and candidate(s). o Mutational analysis (single amino acid(s) or domain) of proteins in auditory and vestibular biology. o Use of purified reconstitution systems to assess protein function, either recombinant or natively purified, involved in auditory/vestibular biology. o Use of fluorescently tagged proteins (either as fusion proteins or protein conjugates; purified tagged or labeled proteins delivered using microinjection) to monitor in vivo intracellular expression/localization and function of auditory/vestibular proteins in relative cellular environments (cultured or in ovo). o Use of single and 2-D SDS/PAGE analysis with auditory and vestibular protein assays. o Use of labeled (radioactive, non-radioactive, quantum dots) proteins with in vitro transcription/translation assays to demonstrate binding associations of auditory and vestibular proteins. o Co-precipitation and immunoprecipitations from both native and purified reconstitution systems, using various combinations of recombinant fusion proteins, such as GST, Myc, etc., immuno-recombinant technologies, native immunoreactive antibodies, and native proteins. o Use of gene/protein knock down technologies, morpholinos or small interfering RNA (siRNA). o Binding assays for determination of direct protein interaction, such as overlays, or other purified protein combination systems. o Use of optical tweezers analyzing proteins important for auditory/vestibular function. o Use of fluorescence resonance energy transfer (FRET) and fluorescence recovery after photobleach (FRAP) technologies studying auditory/vestibular protein interactions. o Use of X-ray crystallographic methods to resolve structure of proteins important in auditory and vestibular biology. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July/August 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. Investigators may submit only a single application for this RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. FUNDS AVAILABLE The NIDCD intends to commit approximately $1.5 million in FY 05 to fund 3 to 4 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $250,000 per year. 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. ELIGIBLE INSTITUTIONS An investigator may only submit a single application in response to this RFA. You may submit an application 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 institutions/organizations o Foreign institutions are not eligible to apply 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 must define the significance of the research to auditory and vestibular biology in a separate paragraph titled: Significance to Auditory and Vestibular Research. The paragraph should scientifically justify the importance of the proposed experiments, and the value of the research to auditory and vestibular biology. Applications without this justification paragraph will be determined as non-responsive and returned without further consideration. In addition, it is anticipated that successful applications will foster collaborative interactions between scientists with signal transduction expertise and with auditory and vestibular neurobiologists. 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: Nancy L. Freeman, Ph.D. 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 Tel: (301) 402-3458 Fax: (301) 402-6251 Email: FreemanN@mail.NIH.gov o Direct your questions about peer review issues to: Chief, Scientific Review Branch NIH/NIDCD Division of Extramural Research National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, EPS Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8683 Fax: (301) 402-6250 o Direct your questions about financial or grants management matters to: Chief, Grants Management Branch NIH/NIDCD Executive Plaza South, Room 400B 6120 Executive Boulevard, MSC-7180 Bethesda, MD 20892 Rockville, MD 20852 (express mail) Telephone: (301) 402-0909 FAX: (301)402-1758 LETTER OF INTENT Prospective applicants are strongly encouraged 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, either hard copy or electronic copy, by the date listed at the beginning of this document. The letter of intent should be sent to: Nancy L. Freeman, Ph.D. 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 Tel: (301) 402-3458 Fax: (301) 402-6251 Email: FreemanN@mail.NIH.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. 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 http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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: http://grants.nih.gov/grants/funding/phs398/labels.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 all copies of the 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, EPS Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8683 Fax: (301) 402-6250 APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDCD. Incomplete and/or nonresponsive applications will not be reviewed. 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 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 written critique o Receive a second level review by the NDCD National 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: SIGNIFICANCE TO AUDITORY AND VESTIBULAR RESEARCH. Does the project clearly detail the importance of the proposed experiments, and the value of the research to auditory and vestibular biology? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. 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: September 24, 2004 Application Receipt Date: October 22, 2004 Peer Review Date: February/March 2005 Council Review: May 2005 Earliest Anticipated Start Date: July/August 2005 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 ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this 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.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices