NOVEL THERAPEUTIC AND PATHOGENETIC STUDIES OF OCULOMOTOR DISORDERS RELEASE DATE: October 28, 2002 RFA: EY-03-001 National Eye Institute (NEI) (http://www.nei.nih.gov) APPLICATION RECEIPT DATES: March 27, 2003, and November 21, 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 Special Requirements o Where to Send Inquiries 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) encourages the submission of investigator- initiated applications to develop novel therapeutic and pathogenetic approaches to disorders that affect ocular motility. These disorders include strabismus syndromes, myasthenia gravis, congenital fibrosis syndromes, congenital nystagmus, and other disorders that compromise eye movement in the orbit and thus limit visual acuity. Many of these disorders, such as strabismus, are common in childhood and can lead to permanent visual loss if uncorrected. Present treatments are largely surgical in nature, with uneven success and the need for repeated surgery. Therapy for symptoms such as pain, pressure, or double vision present in some disorders is solely palliative in nature. The mechanisms of pathogenesis for these disorders is largely unknown. Responses to this announcement may include applications for basic or applied, preclinical or clinical research. Applications may broadly address novel therapeutic strategies and/or new insights into the pathogenesis of oculomotor diseases. RESEARCH OBJECTIVES Eye movement disorders represent a diverse set of diseases that have in common the compromised movement of the eye and related structures within the bony orbit. Extraocular muscle tissue and connective tissues in the periphery and efferent premotor and motor pathways in the central nervous system that drive motor outflow are among the identified targets of this group of diseases. As a group, these diseases differ significantly in etiology from muscular dystrophies and neurodegenerative disorders that affect other skeletal muscles, including Duchenne muscular dystrophy and amyotrophic lateral sclerosis. Extraocular muscle are rarely affected in these latter diseases, and eye movement functions are selectively spared, even in advanced stages of the disease. The etiology of the differential involvement of eye muscles and the oculomotor system in these disorders is unknown. One goal of this Program Announcement is to advance our understanding of this differential sparing of the oculomotor system, particularly as it informs our understanding of oculomotor-targeted diseases. The following examples are not intended to represent an exhaustive listing. They are suggestive of the diverse nature of oculomotor-selective disease and illustrate the need for research to identify the underlying etiologies. Advances in these areas will aid the development of rational therapy and treatment regimens. o Strabismus syndromes include a range of disorders that affect binocular fixation of the eye. Strabismus may lead to amblyopia, which affects three to five per cent of the US population. Patients present with misalignment of the visual axes -- deviation of one eye inward (esotropia) or outward (exotropia) compared to the other eye --resulting in compromised depth perception and binocular vision. Strabismus may be caused by anatomic abnormalities of the orbits, eyes and/or extraocular muscles. Surgical treatment is imperfect, with a 20 - 50% failure rate, necessitating repeat surgeries. Untreated or uncorrected strabismus leads to amblyopia, the permanent loss of binocular vision, and low or reduced visual acuity. Congenital fibrosis extra ocular muscle syndromes (CFEOMs) are rare inherited human strabismus syndromes that also present with limited and restrictive globe movement. There is evidence of extraocular muscle tissue abnormalities secondary to neuropathology in the oculomotor, abducens, and trochlear nuclei. Several genes associated with CFEOMs have been mapped, but most are unidentified and their function is not understood. o Myasthenia gravis is an autoimmune disorder primarily targeting the acetylcholine receptor at the neuromuscular junction of skeletal muscle, leading to muscle weakness and neurodegeneration. The skeletal muscles involved vary; most myasthenia gravis patients have ocular muscle involvement. The fluctuating weakness in the extraocular and facial muscles causes ocular misalignment. The pathophysiology underlying the diverse phenotypes and differential involvement of extra ocular muscles is unknown. o Graves' ophthalmopathy (GO) is the clinical involvement of the eyes seen in Graves' disease, or hyperthyroidism. GO is characterized by an increase in the volume of orbital tissues leading to periorbital edema, exophthalmoses, and extraocular muscle dysfunction. Few treatment options beyond palliative care are available for the ocular pain and double vision that are the clinical symptoms of GO. In severe cases, blindness may result. Autoimmune processes and metabolic insults targeting fibroblasts and fatty connective tissues within the orbit have been proposed as pathologic bases for this disease. On March 7-8, 2001, the NEI hosted a workshop on Craniofacial Muscle Specialization and Disease, bringing together scientists and clinicians from the U.S. and Europe. The group explored what is known about the unique characteristics of extraocular and other craniofacial muscles that render them selectively vulnerable or resistant to disease. The workshop was timely, given recent scientific progress identifying regulatory factors for muscle development and new hypotheses for the role of orbital tissues in eye movement. Advances in noninvasive imaging technology have also had an impact on craniofacial muscle research. The goal of the workshop was to characterize the common features of three unique muscle types -- extraocular, laryngeal, and mandibular -- to build a framework for future research directions. Workshop participants discussed the structure, function, development and biochemistry of these craniofacial muscle classes and the diseases that are craniofacial muscle-selective or craniofacial muscle- resistant. Analyzing the biology and disease phenotypes across these three muscle types is essential to the identification of pathogenetic mechanisms that distinguish craniofacial disease from other skeletal muscle disorders. The workshop concluded with a discussion of research needs in the area of craniofacial muscle biology and disease. The recommendations stressed the importance of collaborative research across multiple disciplines to promote new insights into the pathogenesis of craniofacial-selective and craniofacial-resistant diseases. Summary and Scope The manifestations of disorders of the oculomotor system can be readily and reliably identified in the clinical setting; however, the pathogenesis, therapy, and treatment of these disorders remain problematic. This RFA invites investigators with diverse scientific interests to apply their expertise in basic and applied laboratory and clinical research to enhance our understanding of normal and pathologic ocular motility. Examples of research topics that are considered responsive to this RFA are listed below. This list is not meant to be an exhaustive, exclusive, or delimiting set of topic areas: o Function: Delineation of the functional anatomy of the oculomotor system, including the cellular and molecular organization underlying the biomechanical properties of extraocular muscle during development and in normal and pathological aging of the oculomotor system. o Pathogenetics: Identification of the cellular and molecular targets of oculomotor disease and disease pathogenesis; the differential cellular and molecular organization of extraocular and classical skeletal muscle that is informative in oculomotor system-targeted diseases; the role of the immune system and hormone factors; and candidate disease genes for rare inherited oculomotor disorders. o Development/Regeneration: Understanding the development of the extraocular and related craniofacial muscles and central neural pathways that make them selectively vulnerable or resistant to disease and distinct from that of other skeletal muscle, including the identification of transcription factors, growth factors and apoptotic processes. Explore the use of gene transfer therapies to strengthen extraocular muscle tissue. Utilize stem cells and tissue engineering to produce myogenic and neuronal precursors for restoration of function. o Research Resources: Develop research resources to aid in the identification and treatment of ocular motility disorders. These could include animal models, imaging techniques for improved diagnosis and monitoring of oculomotor disease, ocular kinematical models, newer chemical and molecular markers, new and novel therapeutic surgical approaches. MECHANISM OF SUPPORT This RFA will use NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA has two solicitation dates. 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 dates are December 1, 2003, and July 1, 2004. 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 NEI intends to commit approximately $2 Million in FY2003 and in FY2004 to fund ten to twelve new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five 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 NEI 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 which propose to develop research resources to aid in the identification and treatment of ocular motility disorders should propose a plan to make these resources available to the vision research community. 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: Staff Contact Name Chyren Hunter, Ph.D. Division of Extramural Research National Eye Institute Building EPS, Room 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: 301-402-0528 Email: clh@nei.nih.gov o Direct your questions about peer review issues to: Samuel C. Rawlings, Ph.D. Chief, Scientific Review Branch Division of Extramural Research National Eye Institute Building EPS, Room 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 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 Building EPS, Room 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 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 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. 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, one additional copy of the application must be sent to: Samuel C. Rawlings, Ph.D. Chief, Scientific Review Branch Division of Extramural Research National Eye Institute Building EPS, Room 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: 301-402-0528 Email: rawlings@nei.nih.gov 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 NEI. 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? 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 BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER REVIEW CRITERIA: The adequacy of the proposed plan to share research resources. RECEIPT AND REVIEW SCHEDULE Application Receipt Date: March 27, 2003, and November 21, 2003 Peer Review Date: May/June, 2003, and February/March, 2004. Council Review: October, 2003, and May, 2004 Earliest Anticipated Start Date: December 1, 2003, and July 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.867, 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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