Full Text DE-94-009 RESEARCH ON THE BIOLOGY OF THE PULP NIH GUIDE, Volume 23, Number 34, September 23, 1994 RFA: DE-94-009 P.T. 34 Keywords: Oral Diseases Biology, Molecular Neurophysiology National Institute of Dental Research Letter of Intent Receipt Date: December 15, 1994 Application Receipt Date: January 18, 1995 PURPOSE The National Institute of Dental Research (NIDR) encourages studies leading to a better understanding of the reactions of the pulp-dentin complex in health and disease and how these tissues are involved in responding to various challenges. A thorough understanding of pulp biology, its normal function and physiology, and its pathology and its interaction with the immune system is decisive for the success of operative dentistry and endodontics. The intent of this Request For Application (RFA) is to stimulate research in both basic and applied disciplines of dentistry by multi-methodological approaches. This aim can be achieved through interactions by researchers in such fields as cell biology, neurophysiology, operative dentistry, and endodontics, in academia, government, and industry. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Research on the Biology of the Pulp, is related to the priority area of oral health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit, public and private organizations, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions and organizations are not eligible for the First Independent Research Support and Transition (FIRST) awards (R29). Domestic applications may include international components. Applications from minority individuals and women are encouraged. Applicants must meet special eligibility requirements specified in the pertinent guidelines for the various mechanisms available for support of this program. MECHANISMS OF SUPPORT This RFA will use the National Institutes of Health individual research project grant (R01) and the FIRST (R29) award. The earliest possible date for funding is December 1, 1995. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all other investigator-initiated research grant applications and may be peer reviewed according to the customary peer review procedures. Responsibility for the planning, direction and execution of the proposed research will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. FUNDS AVAILABLE Approximately $800,000 to $1,000,000 in direct costs per year for up to five years will be committed to fund applications that are submitted in response to this RFA. It is anticipated that six to seven awards will be made. The level of funding is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDR, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Over twenty seven million root canal treatments costing more than $3 billion were performed in the United States during the last decade. This number will increase in the future due to population growth and greater numbers of teeth being preserved in older patients. In addition to conditions requiring removal of the pulp, many people experience dentin hypersensitivity in reaction to normally non-painful heat or mechanical stimulation. This has been attributed to a variety of causes, including pulp-dentin pathology, fluid movements through tubules, and excessive nerve excitability. An unusual combination of features makes the dental pulp a unique model for research. The pulp is extensively supplied with nerve fibers, a rich blood supply, and is surrounded by dentin making it an important model for the study of pain, inflammation, and the movement of fluids, bacteria, or their products through the dentinal tubules. The tooth is a hollow, porous hard tissue embedded in bone, projecting through an epithelial membrane into a septic environment. However, in spite of research advances during the last decade, there is limited understanding of the reactions of the pulp-dentin complex during pathologic states such as acute or chronic inflammation, dentin hypersensitivity and nerve excitation. This leads to an inability to diagnose correctly the pathologic state of the pulp according to clinical symptoms. More information is needed on pulpal reactions to restorative procedures and consequent regeneration and repair reactions. Although significant advances in the field have been made, further research is needed. For example, immunohistochemical analyses have led to a better understanding of the mechanisms of antigen presentation and processing, but little is known about pulpal reaction to infection and immunologic responses or pulpal injury, in general, in both normal and immunocompromised patients. Future studies should focus on possible interactions between immune cells in the pulp and the pulpal neurovascular system. Using molecular biology techniques, significant progress has been made in understanding the mechanisms which regulate the terminal differentiation of odontoblasts. However, the mechanism of action of non-collagenous proteins of odontoblast origin in dentogenesis, and in mineralization, in particular, is not well understood. More research is needed in this area to determine how these proteins modulate odontoblast differentiation, migration, adhesion, extracellular matrix production and secretion during both development and repair of dentin. Biochemical analysis is providing information about the neurochemical and humoral factors involved in the control of pulpal blood flow and the factors important in tissue response to damage, but continued studies are needed. Based on recommendations from the NIDR Long-Range Research Plan for the Nineties, as well as recommendations of both the NIDR's Dental Research Programs Advisory Committee and the International Conference on Pathobiology of the Dentin/Pulp Complex, the NIDR plans to strengthen its support of both basic and clinical research in the broad area related to this announcement. Accordingly, applications are invited for individual research project grants, and FIRST Awards, related to, but not limited to, the following areas: Dentin Hypersensitivity o hydraulic conductance of dentinal tubules and the dynamics of hydrodynamic stimulation of mechanoreceptor nerves. o the effect of oral hygiene procedures and non-invasive operative procedures on dentin sensitivity. o the etiology of dentin hypersensitivity as a function of age and immune suppression. Pulpal Reactions to Restorative Materials o the effect of nerve innervation on pulp reactions and pulp healing. o the reactive sprouting of sensory nerves in the pulp as a result of operative procedures and restorative materials. o the effect of hydraulic conductance in the dentinal tubules on the odontoblast layer, the junctional complexes between odontoblasts, and the release of neuropeptides. o the stimulation of secondary odontoblast differentiation and their function in reparative dentin formation. Reactivity of Periapical Pulp Tissue o the difference between the structure and function of the apical portion of the pulp and those of the radicular pulp and the apical periodontal membrane. o the reactivity and healing capacity of periapical tissues. o nerve sprouting in periapical tissue following trauma. o the application of immunohistochemical techniques in the studies of dentin resorption. Normal and Abnormal Dentinogenesis o development of odontoblast cell lines in vitro to elucidate the genetic regulatory mechanisms involved in odontoblast differentiation, modulation and regulation of odontoblast function, secretion of the dentin matrix, and its mineralization to make normal, reparative, and peritubular dentin. o development of cell cultures from undifferentiated pulp cells to study mechanisms involved in their differentiation into functional odontoblasts. o characterization of the protein matrix formed by secondarily differentiated odontoblast and its effect on mineralization of dentin. Dentin/Pulp Complex Reactions o the role of growth factors in normal pulp-dentin development and in pathological states. o cell-cell communication in the pulp among odontoblasts, mesenchymal cells, immune-competent cells, neurons, endothelial and perivascular cells. o the ultrastructure of normal and reparative dentin in response to growth factors and their receptors, as a function of age. o nerve distribution, nerve type and expression of nerve growth factors, cell-cell communication between and among odontoblast, neurons and endothelial cells in health and disease. o assessment of the healing potentials of the pulp at different ages and under a variety of experimental conditions using multi-methodological approaches. o the dynamics of wound healing and repair in the pulp at various ages, including the synthesis and assembly of proteins and their control. Pulpal Reactions: Regulatory and Immunological Factors o immunodefenses in the pulp, including mechanisms of antigen presentation, processing and responses, and changes in these processes as a function of normal aging and in immunocompromised individuals. o development of pulpal and periapical models to identify and characterize the bacteria and bacterial products that cause inflammation. The conditions under which pulpal disease may be reversible. The long-term consequences of chronic periapical inflammation on bone and pulpal nerves(neuromas). o the use of dentinal fluid to indicate the state of pulpal metabolism and/or the presence of pulpal inflammation by measuring changes in the levels of immunoglobulins, cytokines, or lysosomal enzymes. o the expression and regulation of stress or heat shock proteins in pulpal tissues. o determination of the way in which the regulatory proteins modulate odontoblast differentiation, migration, adhesion and matrix synthesis, secretion and its mineralization. Microcirculation o the role of nitric oxide in the control of pulpal blood flow and the effects of free radicals in the pulpal response to injury. Definition of the role of neuropeptides and endogenous mediators of inflammation on neurovascular activity of the normal tooth pulp, following injury and during repair. o development of noninvasive methods to quantitatively determine pulpal blood flow, dentin fluid flow and composition, and sensory functions in animals and humans, in acute and chronic disease states. o the effects of systemic vascular diseases, such as sickle cell anemia and diabetes, on pulpal circulation. o the development of the microcirculation, innervation, and dentin ultrastructure and the effect of aging on the dental pulp. o the transport of various sized molecules through the dentin into the systemic circulation and vice versa, in innervated and denervated teeth. Sensory Physiology o definition of the role and characteristics of inflammatory mediators, neuropeptides, and the autonomic nervous system, in the normal tooth pulp, after injury and during repair. o the mechanisms of sensory transduction within the pulp in normal and pathological states. o clarify the role of A and C fibers in tooth pulp, to determine the central pathways, relay centers, and reflex responses evoked by their activation, to determine the mechanisms of sensory transduction in pulpal nerves in normal and in pathological states. o the effects of tooth pulp pathophysiology on central nervous system processing of pulpal nerve input, such as the relation between tooth pulp loss and chronic pain, referred pain, and altered central nervous system excitability following periapical inflammation. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators also may obtain copies from of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 15, 1994, a letter of intent that includes a descriptive title of the overall proposed research, the name, address, and telephone number of the Principal Investigator, and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIDR staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Joyce A. Reese at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. 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 YES box must be checked and the RFA number and the words, "Research on the Biology of the Pulp" must be typed in Section 2a on the face page of the application. Applications for the FIRST (R29) award must include at least three sealed letters of reference attached to the face page of the original application. FIRST (R29) award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent to: H. George Hausch, Ph.D. Chief, Scientific Review Office National Institute of Dental Research Westwood Building, Room 519 Bethesda, MD 20892 Telephone: (301) 594-7632 Applications must be received by January 15, 1995. If an application is received after that date, it will be returned to the applicant. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by NIDR staff. Incomplete applications will be returned to the applicant without further consideration. If NIDR staff find that the application is not responsive to the RFA, it will be returned without further consideration. 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 NIDR in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. Secondary review will be by the National Advisory Dental Research Council. Major factors to be considered in the evaluation of applications include: o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o availability of resources necessary to perform research; o appropriateness of the proposed budget and duration in relation to the proposed research; AWARD CRITERIA The anticipated date of award is September 1, 1995. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total cost of the project to the NIDR will be considered by NIDR staff and the Council in making funding recommendations. Furthermore, the NIDR appreciates the value of complementary funding from other public and private sources, including foundations and industrial concerns, for activities that will complement and expand those supported by the NIDR. Such circumstances will be considered in making any award. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joyce A. Reese, D.D.S, M.P.H. Extramural Program National Institute of Dental Research Westwood Building, Room 509 Bethesda, MD 20892 Telephone: (301) 594-7648 Direct inquiries regarding fiscal matters to: Ms. Theresa Ringler Extramural Program National Institute of Dental Research Westwood Building, Room 510 Bethesda, MD 20892 Telephone: (301) 594-7629 Inquiries regarding review issues may be directed to Dr. H. George Hausch at the address listed under APPLICATION PROCEDURES. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free work place and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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