OCULAR ALBINISM (OA1) AND RETINAL GANGLION CELL DEVELOPMENT RELEASE DATE: January 14, 2003 RFA: EY-03-003 National Eye Institute (NEI) (http://www.nei.nih.gov) APPLICATION RECEIPT DATE: August 15, 2003 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 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 Eye Institute (NEI) wishes to promote research on the pathogenesis and treatment of Ocular Albinism 1 (OA1) and related developmental disorders. Individuals with OA1 demonstrate a congenital reduction or absence of melanin pigment in the eye, which results in poor visual acuity. Recent research on the enzymes and genes involved in the production of melanin has provided a deeper understanding of the molecular genetic defects associated with albinism. The pathology of OA1 also includes developmental disturbances in retinal ganglion cell (RGC) axon development. These lead to visual abnormalities such as nystagmus, strabismus, foveal hypoplasia, photophobia, and refractive errors. This Request for Applications (RFA) solicits basic, translational, and clinical research projects which will provide a clearer understanding of OA1 as well developmental retinal disorders affecting the number and routing of central visual projections. Knowledge gained by research in this area will provide the scientific rationale for new forms of diagnosis and treatment. RESEARCH OBJECTIVES Background Albinism refers to a heterogeneous group of congenital disorders in melanin pigment biogenesis. These conditions are characterized by a reduction or total absence of pigment in the hair, skin, and eyes. Ocular albinism is a subgroup of disorders arising from a reduction of melanin pigment in the retinal pigment epithelium (RPE). Pigment deficits in the RPE also lead to a reduction in the number and distribution of photoreceptors and other retinal cells by affecting the mechanisms controlling cell proliferation during the early development of the retina. Such hypo-pigmentation of the RPE is associated with the misrouting of RGC axons at the optic chiasm. This results in abnormal projections to visual centers in the thalamus and cortex. OA1 is the most common form of ocular albinism. It is an inherited, X-linked disorder wherein the RPE lacks pigment while the skin and hair are normal. The pathology of OA1 includes disturbances in the factors which affect the number of retinal cells and their proliferation during early retinal development. These errors in RGC axon development and guidance lead to developmental abnormalities such as myopia. A less frequently occurring form of ocular albinism, oculocutaneous albinism or OCA, is a group of congenital, mostly autosomal recessive but occasionally autosomal dominant disorders. OCA is characterized by a generalized disruption in melanin pigment synthesis in the hair, skin, and eyes. OCA and OA1 give rise to a similar constellation of visual disorders. A number of developmental disorders related to OA1 affect formation of the optic nerve. These include the Angelman, Apert, Ch diak-Higashi, Griscelli, Hermansky-Pudlak, Optic Nerve Hypoplasia (ONH), Prader-Willi, Septo-optic Dysplasia (SOD), and Waardenburg syndromes. The pathogenesis of these conditions includes factors affecting the number of retinal cells and their proliferation during early retinal development. ONH and SOD are not associated with defects in melanin metabolism. Research Objectives and Scope The goal of this RFA is to stimulate and support research that can provide a clearer understanding of developmental retinal disorders, misrouting of optic nerve axons, and abnormalities of the optic nerve related to the pigment deficits found in ocular albinism and similar developmental disorders. Such research may require interdisciplinary studies including neuroscientists, cell biologists and clinicians. Studies using human tissue, appropriate animal models, and clinical subjects are encouraged. However, clinical trials and broad population-based studies will not be supported by this initiative. Suggested research topics may include, but are not limited to: o Development of new treatments for OA1 and related diseases. o Determination of the role of pigmentation deficits on the development of the retina, including neurogenesis, differentiation, and distribution of retinal cells. o Identification of the influence of tyrosinase expression and melanin production on RPE and RGC fate. o Study of the development and distribution of retinal cells. o Study of the genetics of albinism as it relates to the visual system and misrouting of retinal ganglion cell axons to their central targets. o Elucidation of the relationship between hypo-pigmentation and refractive errors. o Determination of how pigment deficits in the in the RPE lead to abnormalities of axonal guidance in the developing visual system. o Determination of the developmental mechanisms associated with OHN and SOD which lead to reduced numbers of RGC axons and related abnormalities of the optic nerve. o Determination of the function of the OA1 gene product. o Development of a clearer understanding of the genetic mechanisms necessary for the normal biogenesis of RPE melanosomes in visual tissues. o Development of new diagnostic tests for OA1. o Determination of the mechanisms which disrupt retinal foveal development in OA1 and related disorders. 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 April 1, 2004. This RFA uses just-in-time concepts. It also uses the modular 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 format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE The NEI intends to commit approximately $1.5 million in FY 2004 to fund approximately two to four new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs commensurate with the proposed work. 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 NEI 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. ELIGIBLE INSTITUTIONS 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 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. 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: Peter A. Dudley, Ph.D. Division of Extramural Research National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: pad@nei.nih.gov o Direct your questions about peer review issues to: Samuel C. Rawlings, Ph.D. Chief, Scientific Review Branch National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda MD 20892-7164 Telephone: (301) 496-5561 FAX: (301) 402-0528 Email: rawlings@nei.nih.gov o Direct your questions about financial or grants management matters to: William W. Darby Grants Management Officer National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda MD 20892-7164 Telephone: (301) 496-5884 FAX: (301) 496-9997 Email: wwd@nei.nih.gov 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 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. o 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. o 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/label-bk.pdf. o 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: Samuel C. Rawlings, Ph.D. Chief, Scientific Review Branch National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda MD 20892-7164 Telephone: (301) 496-5561 FAX: (301) 402-0528 Email: rawlings@nei.nih.gov o 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 (IC). Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 NEI 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 applications will be discussed and assigned a priority score o Receive a second level review by the National Advisory Eye 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? o ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: (1) 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. (2) 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) (3) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Application Receipt Date: August 15, 2003 Peer Review Date: October, 2003 Council Review: January, 2004 Earliest Anticipated Start Date: April 1, 2004 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 o 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://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 Office of Management and Budget (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. o INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (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). 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 http://grants.nih.gov/grants/funding/children/children.htm. o 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. o HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm 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 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. o PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 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. o 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. o 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. o AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.387, 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 PHS Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://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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