RESTORATION OF OROFACIAL TISSUES: A BIOMIMETIC/TISSUE ENGINEERING APPROACH RELEASE DATE: August 22, 2002 RFA: DE-03-004 National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidr.nih.gov/) LETTER OF INTENT RECEIPT DATE: October 20, 2002 APPLICATION RECEIPT DATE: November 20, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms 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 purpose of this RFA is to encourage biomimetics and tissue engineering research in the areas of orofacial tissue and organ repair and regeneration. The ultimate goal of this initiative is a systems approach to the design and development of new biocompatible/inductive materials that can stimulate cells and tissues to regenerate and/or materials that can become integrated into the body. In particular, this initiative encourages: o biomimetic/tissue engineering approaches for the restoration/regeneration of tooth and periodontal structures; o tissue engineering and stem/progenitor cell approaches for the construction of an artificial salivary gland and for the repair/regeneration of Temporomandibular Joint (TMJ) structure; and o use of new diagnostic imaging technologies and novel molecular imaging probes to monitor key events during tissue repair/regeneration. In the context of this initiative, integrative, multidisciplinary/interdisciplinary research approaches from several different scientific disciplines such as cell and molecular biology, genetics, physics, engineering, computer and clinical sciences and other relevant systems are encouraged. Applicants may propose hypothesis-driven, discovery-driven, developmental, or design-directed research. RESEARCH OBJECTIVES Background The orofacial tissues and organs pose particularly interesting challenges in repair/regeneration because of: i) a complex nerve supply fine-tuned to serve special and general senses and to control muscles of speech, respiration, mastication, and emotional expression; ii) a rich blood supply to support high energy demands; iii) the presence of the most complex joint in the body; and iv) a number of unique organs and tissues: salivary glands, tongue, teeth and periodontal tissues. Moreover, any interventions to restore these tissues must contend with aesthetics and the importance of the face as the projected image of the individual to the world. As we enter the 21st century, the field of biomaterials is becoming one of the most exciting areas of materials science and engineering. There is currently "fresh energy" in this subject brought about by the availability of information from the genome project, and the availability of human adult and embryonic stem cells. Such advantages allow scientists to design and fabricate new materials following and even improving, the work of nature to meet the challenges of repairing and restoring orofacial tissues and organs. This initiative encourages applications that make use of the recent advances in biology, chemistry, physics and engineering to design functional materials that simulate the natural biological environment in order to facilitate: i) restoration/regeneration of tooth and periodontal structures; ii) construction of an artificial salivary gland; and iii) repair/regeneration of TMJ structure. This initiative also encourages the use of new imaging technologies and novel molecular imaging probes that can provide in vivo imaging of the biological processes during tissue repair and monitor treatment outcomes. i. Restoration/regeneration of tooth and periodontal structures. About 30% of the population age 65 and older is completely edentulous (toothless). Standard treatment of tooth loss involves prosthetic devices (dentures). Although these devices are initially functional and restore the ability to chew, as the individual becomes older they present problems with fit and aesthetics due to the loss of underlying bone. Replacement of teeth by dental implants provides more natural and stable function than dentures, but implants are not fully biocompatible and must be periodically replaced by surgical procedures. In addition, many Americans suffer from periodontal disease and missing teeth. For example, by the age of 35 nearly every person has some degree of gingival inflammation or periodontal disease, and 15% of the total U.S. population has severe periodontal disease. At present, periodontal diseases are treated primarily by surgical methods, but restoration of normal function is generally slow, imperfect, and temporary. Therefore, there are major clinical problems in the long- term management of these disorders. In the area of tooth structure, development and formation, the NIDCR has supported years of research that now promise new strategies for tooth repair and regeneration. Significant progress has been achieved in our understanding of tooth formation. A major advance has been the identification of specific signals required for development of the tooth at the mechanistic level. A hierarchy of reciprocal tissue signals has been identified, and the consequences of loss or excess function are now recognized for several genes in critical pathways. Breakthroughs in understanding enamel, dentin and cementum formation have also occurred. Moreover, new relevant genes and structural proteins have been discovered, and research has been accelerated by information from the human and mouse genome projects. Besides identifying crucial genes and their expression at different times of tooth structure development, scientists are starting to decipher the mechanisms of inorganic templating that direct mineral crystal formation and the final form of natural composites. To mimic the properties or structures of these natural materials for efficient repair or replacement of teeth and bone, scientists will need to develop efficient biomimetics-based designs. Effective repair/restoration of teeth and periodontal tissues requires balanced connective tissue growth, coverage by epithelium, and formation of an effective tissue seal with teeth at the gum line. Substantial advances in our understanding of cell adhesion and the extracellular matrix molecules that support and regulate nearly all cells provide many potential approaches to designing biomimetics. Examples include scaffolds that mimic extracellular matrix architecture, adhesives and anti-adhesives specific for individual tissues, and controlled-release depots for molecules that regulate growth, tissue rearrangement, and differentiated function. ii. Construction of an Artificial Salivary Gland Loss of salivary gland parenchyma and consequent inability to make saliva affects an individual's quality of life. Currently, there is no effective treatment for this condition. Saliva is a remarkable, multipurpose fluid whose presence most of us take for granted. Yet each year, it is estimated that about 40,000 people suffer a loss of salivary gland function as a result of radiation treatment for head and neck cancer. Although the treatment may save and prolong life, it can permanently damage salivary glands located in the field of radiation. In addition, it is estimated that more than one million Americans (primarily women) are afflicted with Sjögren's syndrome, an autoimmune disease whose symptoms include dry mouth and dry eyes. Whether salivary glands are irreparably damaged by a disease such as Sjögren's syndrome, or by treatment such as radiation for head and neck cancer, the resulting loss of saliva flow markedly impairs the quality of life. Without adequate saliva, patients may experience difficulty speaking, chewing and swallowing. They may also experience rampant tooth decay, mucosal infections such as candidiasis, loss of taste, and considerable oral discomfort. This initiative encourages the application of state- of-the-art methodologies including the use of adult and embryonic stem cells for the regeneration of the salivary gland parenchyma and restoration of its secretory function. iii. Development of New Therapeutic Strategies for TMJ Repair and Regeneration. Epidemiological data suggest that approximately 10.8 million American adults experience symptoms associated with Temporomandibular Joint Disorders (TMJDs). Anatomically, the TMJ consists of the mandibular condyle, the mandibular fossa and articular eminence of the temporal bone, the muscles of mastication and the associated connective tissues, including the articular disk. Abnormalities of each of these structures have been implicated with TMJDs and, in many cases, these structures need to be repaired or regenerated. Bone, connective tissue, and muscle are potentially repairable through the use of mesenchymal stem cells. Pluripotential stem cells have the inherent ability to be transformed into many different types of tissue, depending on the growth environment to which they are subjected. Current evidence suggests that stem cell-mediated repair of a damaged structure is best performed relatively soon after the initiating event. Presumably, the differentiation of stem cells into the phenotype(s) of the injured tissues is due to the presence of soluble factors (e.g., growth factors, chemokines, etc) that are released from the injured tissues. Recent work with autologous mesenchymal stem cells in animal models, both with and without scaffolds, has demonstrated the ability of these cells to transform into the component tissues of a joint to effect repair of experimentally induced defects. Mesenchymal stem cells can be harvested from bone marrow as well as from fat via liposuction. The latter represents an easily obtainable source of autologous stem cells for therapeutic needs. As mentioned earlier, muscles not only control facial expressions but are also key components of the TMJ. Muscle is a highly ordered structure, composed of tubes of basal lamina in which differentiated myocytes reside. Through a complex system of neuromuscular junctions, each myocyte is synaptically connected to the central nervous system to effect volitional motor control. The matrix scaffolding of a skeletal muscle is extraordinarily complex and crucially important if functional neuromuscular junctions are to be replicated. In order to design synthetic or naturally derived matrices that promote formation of functional facial musculature, advances in understanding muscle matrix formation are necessary. Therefore, research should be directed toward understanding the basal lamina of skeletal muscle, followed by engineering a matrix that allows regeneration of normal muscle fibers from the stem cells that exist in adult skeletal muscle. Imaging technologies and novel molecular imaging probes could provide in vivo imaging of the biological processes (e.g., cell movements, enzymatic activity and gene expression patterns) from stem cells to the formation of the tissue. The use of such technologies together with fluidics, optics and electronics could enable development of noninvasive sensing systems to pinpoint key events that mark the onset of TMJDs and could also be used to monitor treatment outcomes, and key events in stem cell treatment. Scope The objectives and scope of this initiative are to support basic and applied research for the design and development of new biocompatible/inductive materials for the repair and regeneration of tooth and periodontal tissues, salivary glands and TMJ structures. Research topics might include but are not limited to the following: o Design of biodegradable scaffolds to serve as platforms for cells to organize tissues for repair and regeneration of teeth and periodontal tissues. Biomimetic replacements for various collagens, fibronectin, laminin, or proteoglycans could be created that combine activities from several molecules, have specificity for anchoring only certain cells, and possess inherent resistance to proteolytic enzymes. o Definition of the structural architecture and molecular interactions that specify organic-inorganic (biological-mineral) interfaces at all hierarchical levels (i.e., from nanoscale to tissue scale). For example, it is essential to establish how enamel, dentin, and cementum proteins serve as templates for mineral deposition and the different steps involved in the processes of biomineralization and strengthening of tooth structures. o Design of bio-inspired dental composite/ceramic materials through biomimetic principles of hierarchical self-assembly. For example, development of tooth restorative materials with nanoscale-oriented deposition of materials, and biomimetic polymers that regulate form and provide protection against fracture, which can mimic or surpass the properties of tooth enamel. o Use of biological principles to design and fabricate materials which will accelerate connective tissue regrowth while restraining epithelial overgrowth during repair of diseased periodontal tissues. Subsequently, these materials should accelerate the later phases of periodontal tissue restoration; i.e., closing the epithelial gap to the tooth surface and subsequently forming an anti-bacterial seal. o Application of principles of self-assembly and cell adhesion to modify the surface chemistry of synthetic tooth replacements. For example, development of adhesive surfaces using peptides or mimetics that mediate selective adhesion to connective tissue or oral epithelium, which can provide fully biocompatible attachment surfaces for implantable materials. o Use of biomimetic principles to develop anti-fouling and self- cleaning coatings for oral biomaterial surfaces to prevent or disrupt formation of biofilms and to enhance defenses against bacteria. o Develop methods (e.g., scaffolds incorporating gradients of regulatory factors and bioreactor control of biochemical and physical signals) to induce salivary stem/progenitor cell differentiation and in vitro assembly of a functional acinar unit prior to transplantation. o Develop biodegradable synthetic polymers for gene transfer and for continuous release of fully active molecules that function to stabilize the salivary nascent tissue at the implant site. o Develop effective drug delivery systems using biomimetic principles based on salivary proteins. For example, mucins with their highly branching oligosaccharide moieties, reminiscent of dentritic polymers might be engineered to serve as effective drug delivery systems for anticancer and other drugs. o Identify, isolate, culture and characterize multipotent stem cells from adult tissue types for repair of TMJ associated structures (i.e., bone, cartilage, muscle). o Determine factors that drive individual stem cells into different cellular phenotypes relevant to TMJ reconstruction (e.g., muscle, bone, cartilage etc.). o Conduct comparative studies between adult somatic cells with pluripotential properties with the aim of defining a rigorous phenotype of somatic stem cells that can be used in joint reconstruction. o Develop clinically relevant small and large animal models to make use of the concept of stem cell plasticity for TMJ reconstruction. o Develop "smart" polymers that mimic the extracellular matrix in serving as scaffolds for stem cell transplantation. These polymers could also serve as reservoirs and delivery systems for regulatory molecules such as growth factors, with the capability of releasing precise amounts of these molecules only when subjected to local pressure from TMJ movements. o Use in vivo molecular imaging technologies for characterizing molecular processes and screening drugs in genetically engineered animal models of TMJDs, and for determining the interactions of implantable materials with biological systems (e.g., material biocompatibility and bioactivity in the host environment). o Develop imaging agents, probes, and radiopharmaceuticals that identify TMJ defects at the cellular and molecular level. Because of the nature of the research required to stimulate the design and development of a new generation of biomaterials, it is expected that potential applicants will include investigators with expertise in biology, bioengineering, physics, chemistry, bioimaging, bioinformatics and clinical sciences. MECHANISM OF SUPPORT This RFA will use the NIH Research Project Grant (R01) and the Exploratory/Developmental research grant (R21) mechanisms. 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 30, 2003. This RFA uses just-in-time concepts. Applications for the R01 and R21 mechanisms use the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, for this RFA, use the modular format. The R21 proposals should have the potential for truly groundbreaking impact. Use of this mechanism by investigators with expertise in fields (e.g., tissue engineering, biomimetics, imaging) other than dental, oral and craniofacial research experience who wish to explore new biomedical approaches to address basic and applied research questions is encouraged. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. FUNDS AVAILABLE The NIDCR intends to commit approximately $3,000,000 in FY 2003 to fund 8-10 new grants in response to this RFA. An R01 applicant may request a project period of up to 4 years and a budget for direct costs of up to $250,000 per year. An R21 applicant may request a project period of up to 2 years and a budget for direct costs of up to $125,000 per year. The R21 application must include milestones that will be used to judge the success of the proposed exploratory research. An R21 application should not exceed 10 pages for the research plan. 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 FY 2003 financial plans of the NIDCR provide support for this program, awards pursuant to the 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 if your institution has any of the following characteristics: o For-profit or non-profit organization o Public or private institutions such as universities, colleges, hospitals, and laboratories o National 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: Eleni Kousvelari, DDS, D.Sc., Cellular & Molecular Biology, Physiology & Biotechnology Branch National Institute of Dental and Craniofacial Research National Institutes of Health Building 45 Room 4AN-18A Bethesda, MD 20892 Telephone: (301) 594-2427 FAX: (301) 480-8318 Email: kousvelari@de45.nidr.nih.gov o Direct your questions about peer review issues to: H. George Hausch, Ph.D. Acting Director, Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health 45 Center Drive, Room 4AN-44F Bethesda, MD 20892-6402 Telephone: (301) 594-2904 FAX: (301) 480-8303 Email: George.Hausch@nih.gov o Direct your questions about financial or grants management matters to: Mr. Hoai Doan Grant Management Specialist National Institutes of Dental and Craniofacial Research National Institutes of Health 45 Center Drive, Room 4AN-32J Bethesda, MD 20892-6402 P: (301)594-4800 F: (301)480-8301 Email: hoai.doan@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDCR and CSR staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. It is preferred that the letter of intent be sent electronically to kousvelari@de45.nidr.nih.gov If necessary, the letter of intent can be sent by regular mail to Dr. Eleni Kousvelari, listed in the WHERE TO SEND INQUIRIES section of this announcement. 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) 435-0714, 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/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. H. George Hausch Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health 45 Center Drive, Room 4AN-44F Bethesda, MD 20892-6402 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 NIDCR. 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 CSR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate Institute 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? To what degree does the technology support the needs for research on biological or disease processes? (2) APPROACH: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate for the design and development of new materials? Does the applicant acknowledge potential problem areas and consider alternative tactics? If appropriate, what is the time frame for developing the proposed new materials and what is the suitability of this time frame for meeting the community's needs? How easy will it be to use the proposed materials? If industrial partnerships are proposed, how will they facilitate and complement the development of new biomaterials? (3) INNOVATION: Does the project address discovery or technology development that represents innovation for the field of orofacial tissue repair? Does the project challenge existing paradigms or employ novel concepts, approaches, or methods? What are the innovative applications of the proposed fundamental discovery, technology, or tools? (4) INVESTIGATOR: Does the principal investigator possess appropriate experience and capabilities to direct and carry out this work? Is the experience level of the principal investigator, other researchers, or collaborators appropriate for the proposed effort? (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 or collaborative agreements? 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 BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. For R21 applications, the scientific review group will evaluate the feasibility milestones that would justify progression to a future R01. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: October 20, 2002 Application Receipt Date: November 20, 2002 Peer Review Date: February/March 2003 Council Review: May/June 2003 Earliest Anticipated Start Date: July 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (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 PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://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 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 initiative 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. 93.121 (NIDCR) 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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