This Program Announcement Expires on June 1, 2005 unless reissued. NOVEL APPROACHES TO CORNEAL TISSUE ENGINEERING RELEASE DATE: January 30, 2002 PA NUMBER: PA-02-053 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Eye Institute (NEI) (http://www.nei.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Eye Institute (NEI) invites submission of investigator-initiated research applications to explore new approaches that could lead to enhanced engineering of corneal tissues. The cornea is the transparent, convex, outermost part of the eye and is the main refractive element of the visual system. The cornea consists of three distinct layers: a tear-bathed, stratified layer of epithelial cells; a thick stroma of connective tissue sparsely embedded with quiescent fibroblasts; and an inner epithelial layer, called the endothelium, that is bathed by the aqueous humor. The purpose of this announcement is to stimulate interest in all aspects of corneal tissue engineering. This includes studies of early developmental processes to delineate the interactions between individual corneal tissue layers, the biomechanical properties of the stroma, cellular control of matrix deposition, control of corneal growth and maturation, and studies of synthetic replacement materials. The NEI wishes to attract new research talent to an area of reparative medicine that has outstanding potential to fulfill future needs in corneal transplantation. Multidisciplinary approaches are encouraged. RESEARCH OBJECTIVES Background In the United States, over 45,000 corneal transplants are performed each year. Due in part to the relative inaccessibility of the avascular cornea to cells of the immune system, corneal grafts require only local immune suppression and represent the most successful transplants. Generally, the two-year survival rate in non-vascularized (low risk) corneas exceeds 90%. With improved techniques, immunosuppression, and control of neovascularization in some high-risk patients, it is expected that the number of candidates for corneal transplantation and thus the need for corneal tissue will increase. Some inconsistency in the success rate of corneal transplantation may be attributable to variable availability of high quality donor tissue. Corneas are harvested and stored in specially designed media, and range in quality depending upon medical conditions before death, length of storage, and surgical technique. Furthermore, the availability of acceptable donor tissue is expected to decrease with widespread use of laser in situ keratomileusis (LASIK) for correcting refractive errors, because these surgically treated corneas are unacceptable donor tissue. With over a million refractive surgeries performed each year in the US, an increasing number of candidate donors will become ineligible as the proportion of the population treated with LASIK increases. Finally, with over six million people blinded worldwide by infectious diseases of the cornea, there is a tremendous unmet need for corneal tissue due, in part, to the lack of donor tissue. The goal of tissue engineering is to repair or replace tissues and organs by delivering proteins, nucleic acids, cells, scaffolds, or newly constructed tissues to diseased or damaged areas. Progress has been made in the synthesis and regeneration of some structural tissues such as skin, cartilage, and bone. Recent advances have yielded a viable corneal equivalent tissue thereby providing a "proof of concept", but these constructs cannot be used effectively for tissue replacement as currently designed. Formidable barriers remain, particularly the construction of stromal equivalents with the proper dimensions, transparency, and biomechanical properties. Summary and Scope The goal of this initiative is to alert the scientific community, especially those not typically involved with corneal research and/or tissue engineering, that a number of approaches may be fruitful in advancing our understanding of fundamental processes essential for generating viable corneal tissues. Improvements in our understanding of all three major tissues of the cornea -- the epithelium, stroma, and endothelium -- are necessary to speed development of an effective corneal replacement tissue. Thus, a variety of disciplines may be applicable to these studies and the NEI encourages a broad spectrum of approaches including but not limited to the following: 1. Embryological and developmental biology of the cornea. The stroma and endothelium develop from mesoderm-derived cells, but the epithelium develops from neural ectoderm. Although it is well known that the presence of the developing lens is essential for corneal development, little is known about the signals and interactions between corneal cell layers during development that lead to a transparent, multilayered structure. Clues for advancing in vitro growth of corneal tissues may be derived from studies such as: o Identification of regulatory pathways, including signaling and intercellular communication. o Understanding molecular cross-talk between the developing lens and surface ectoderm. o Delineation of developmental changes in gene and protein expression. o Development of new genetic resources for probing early developmental processes. o Identification of anti-angiogenic factors in the developing cornea. o Delineation of proliferative capacity and cell cycle regulation during corneogenesis. o Identification of spatio-temporal features of stem cell specification. o Delineation of apoptotic processes involved in corneal development. o Understanding the molecular details of neural crest – mesenchymal transformation. 2. Corneal collagen matrix biology. The matrix provides scaffolding for keratocyte migration, cellular cross-talk, and refraction. Studies may include: o Biomechanical properties of developing collagen matrices. o Influence of fibril length and orientation on corneal biomechanical properties. o Influence of proteoglycans on stromal tissue physiology. o Fibroblast migration and proliferation in three-dimensional collagen matrices. o Molecular cross-talk between the cellular and extracellular environment during corneogenesis. o Development of new or modification of existing stromal replacement materials. MECHANISM OF SUPPORT This PA will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period for an application submitted in response to this PA may not exceed five years. This PA 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. ELIGIBLE INSTITUTIONS You may submit an application if your institution has 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 your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Richard S. Fisher, Ph.D. Division of Extramural Research National Eye Institute Building EPS, Room 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-5301 FAX: (301) 402-0528 Email: rf75s@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) 496-5884 FAX: (301) 402-0528 Email: wwd@nei.nih.gov SUBMITTING AN APPLICATION Applications must be prepaid using the Public Health Service (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) 435-0714, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES Applications submitted in response to this PA will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. 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. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least six weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH Submit a signed, typewritten original of the application, including the checklist, and five 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) APPLICATION PROCESSING Applications must be received by or mailed before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate 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: 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. 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) DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program 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 (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 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 PATICIPANTS 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 http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PATICIPANTS: 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. 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. 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 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 PA 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 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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