Date: September 23, 2005
Place: Building 31C, Conference Room 6C10
National Institutes of Health
Bethesda, Maryland
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
The 180th meeting of the National Advisory Dental and Craniofacial Research Council NADCRC) was convened on September 23, 2005, at 8:30 a.m., in Building 31C, Conference Room 6C10, National Institutes of Health (NIH), Bethesda, Maryland. The meeting was open to the public from 8:30 a.m. to 12:15 p.m., followed by the closed session for Council business and consideration of grant applications from 1:30 p.m. until adjournment at 3:00 p.m. Dr. Lawrence A. Tabak presided as Chair.
Members Present:
Dr. Eli I. Capilouto
Dr. Louise T. Chow
Dr. Nereyda P. Clark
Dr. Matthew J. Doyle
Dr. Augusto R. Elias-Boneta
Dr. Linda G. Griffith
Dr. Mark C. Herzberg
Dr. Josephine Lai
Dr. Jon D. Levine
Dr. Anne S. Lindblad (by telephone)
Dr. Francis L. Macrina
Dr. Michael Reed
Dr. Tracy A. Scott
Members of the Public Present:
Mr. Jack Bresch, Associate Executive Director, American Dental Education Association (ADEA), Washington, DC
Dr. Aida A. Chohayeb, Women Network Collective Research, Washington, DC
Dr. Robert J. (Skip) Collins, Deputy Executive Director, International Association for Dental Research (IADR) & American Association for Dental Research (AADR), Alexandria,VA
Dr. Frank A. Kyle, Jr., Manager, Legislative and Regulatory Policy, ADA, Washington, DC
Ms. Gina Luke, Director, State Government Relations and Advocacy Outreach, ADEA, Washington, DC
Ms. Myla Moss, Director, Congressional Relations, ADEA, Washington, DC
Dr. Gary L. Pannebecker, Chair, Dental Professional Advisory Committee (DePAC), U.S. Public Health Service, Rockville, MD
Dr. Daryl Pritchard, Director of Legislative Affairs, IADR & AADR, Alexandria, VA
Dr. Philip R. Stashenko, Senior Member of Staff, The Forsyth Institute, Boston, MA
Federal Employees Present:
National Institute of Dental and Craniofacial Research:
Dr. Lawrence A. Tabak, Director, NIDCR
Dr. Robert C. Angerer, Scientific Director, Division of Intramural Research (DIR)
Dr. Albert Avila, Director, Office of Education, DIR
Ms. Carolyn Baum, Committee Management Specialist and Council Secretary, Office of the Director (OD)
Dr. Sangeeta Bhargava, Health Scientist Administrator and Program Director, Immunology and Immunotherapy Program, Division of Basic and Translational Sciences (DBTS)
Dr. Henning Birkedal-Hansen, Acting Deputy Director, NIDCR
Dr. Norman S. Braveman, Executive Secretary, NADCRC, and NIDCR Board of Scientific Counselors, and Assistant to the Director, OD
Dr. Patricia A. Bryant, Health Scientist Administrator and Program Director, Behavioral and Social Science Research Program, Clinical Research Branch (CRB), Division of Clinical Research and Health Promotion (DCRHP)
Dr. María Teresa Canto, Health Scientist Administrator and Program Director, Epidemiology Research Program, CRB, DCRHP
Mr. Hong T. Cao, Grants Management Specialist, Grants Management Branch (GMB), Division of Extramural Activities (DEA)
Dr. Lois K. Cohen, Associate Director for International Health, NIDCR, and Director, Office of International Health (OIH)
Mr. George J. Coy, Chief, Financial Management Branch (FMB), Office of Administrative Management (OAM)
Mr. Kevin L. Crist, Grants Management Specialist, GMB, DEA
Ms. Mary Daley, Chief Grants Management Officer, GMB, DEA
Ms. Yvonne H. du Buy, Associate Director for Management, and Chief, OAM
Dr. Isabel Garcia, Acting Director, Office of Science Policy and Analysis (OSPA), andCo-Director, Residency Program in Dental Public Health at NIDCR, DCRHP
Dr. Kevin Hardwick, International Health Officer, OIH, and Special Assistant for Research Infrastructure and Curriculum Development, OD
Dr. Kathy L. Hayes, Planning Officer, OSPA
Dr. Rosemarie Hunziker, Director, Technology Development and Industrial Relations Program, Center for Biotechnology and Innovation (CBI)
Ms. Lorrayne Jackson, Extramural Research Analyst and Outreach Specialist, OD
Dr. Lynn M. King, Scientific Review Administrator, Scientific Review Branch (SRB), DEA
Dr. Eleni Kousvelari, Acting Director, CBI
Dr. John W. Kusiak, Health Scientist Administrator and Program Director, Molecular and Cellular Neurobiology Program, DBTS
Dr. James Lipton, Senior Advisor to the Chief Dental Officer, U.S. Public Health Service
Dr. Yujing Liu, Scientific Review Administrator, SRB, DEA
Ms. Carol Loose, Budget Analyst, FMB, OAM
Dr. Dennis F. Mangan, Acting Deputy Director, DBTS, and Chief, Infectious Diseases and Immunity Branch, DBTS
Ms. Amy McGuire, Grants Management Specialist, GMB, DEA
Ms. Gladys Melendez-Bohler, Management Analyst, OAM
Dr. Richard L. Mowery, Chief, CRB, DCRHP
Dr. Mostafa Notka, Health Scientist Administrator and Program Director, AIDS and Oral Manifestations of Immunosuppression Program, DBTS
Dr. Ruth Nowjack-Raymer, Health Scientist Administrator and Program Director, Health Disparities Research Program, DCRHP
Ms. Helen Pham, Grants Management Specialist, GMB, DEA
Ms. Rebecca Roper, Scientific Review Administrator, SRB, DEA
Ms. Diana Rutberg, Grants Management Specialist, GMB, DEA
Ms. Soheyla Saadi, Scientific Review Administrator, SRB, DEA
Dr. Ann L. Sandberg, Acting Director, DBTS
Dr. Yasaman Shirazi, Health Scientist Administrator and Program Director, Epithelial Cell Regulation and Transformation Program, DBTS
Dr. Lillian Shum, Health Scientist Administrator and Program Director, Physiology, Pharmacogenetics, and Injury Program, DBTS
Dr. Rochelle Small, Health Scientist Administrator and Program Director, Developmental Biology and Mammalian Genetics Program, DBTS
Ms. Traci Walker, Committee Management Assistant, OD
Other Federal Employees:
Dr. Mary E. Kerr, Deputy Director, National Institute of Nursing Research, NIH
Ms. Vanessa Thomas, Analyst, U.S. Public Health Service
Dr. Tim Ward, Legislative Assistant, Department of Education and Research, Department of Veterans Affairs
OPEN PORTION OF THE MEETING
I. CALL TO ORDER
Dr. Lawrence A. Tabak, Director, NIDCR, called the meeting to order and welcomed everyone. He invited the guests to introduce themselves. Dr. Tabak mentioned that three Council members are completing their terms on the Council. He thanked Drs. Louise T. Chow, Nereyda P. Clark, and Francis L. Macrina for their services and presented each with a certificate of appreciation and a small gift. Dr. Tabak noted that the nominations of three new members have been confirmed. These members—Drs. Marianne Bonner-Fraser, Cecile Feldman, and Philip Stashenko—will join the Council in January 2006.
Dr. Norman S. Braveman, Executive Secretary, NADCRC, referred the Council to the published report of the NIDCR Working Group on Functional Oral Health Literacy. The report, entitled "The Invisible Barrier: Literacy and Its Relationship with Oral Health," appeared recently in the Journal of Public Health Dentistry (vol. 65, no. 3, summer 2005, pp. 174-82). Copies were provided to the Council and were available at the Council meeting.
II. APPROVAL OF MINUTES
The minutes of the Council’s meeting on June 10, 2005, were considered and unanimously approved.
III. FUTURE COUNCIL MEETING DATES
The following dates for future Council meetings were confirmed:
January 23, 2006
May 22, 2006
September 18, 2006
January 22, 2007
May 18, 2007
September 24, 2007
IV. REPORT OF THE DIRECTOR
Dr. Tabak announced a major organizational change at NIDCR, two NIH initiatives, and the formation of a panel to review the NIDCR intramural research program. He elaborated on a presentation he recently gave to the NIH leadership on the balance between "large"-scale and "small"-scale science. Dr. Tabak’s remarks supplemented his written Director's Report, which was provided to Council and was made available at the meeting (see Attachment III).
Reorganization of NIDCR Extramural Program
Dr. Tabak reported that NIDCR has reconfigured its extramural program. On October 1, 2005—the beginning of Fiscal Year (FY) 2006—NIDCR's three extramural divisions will become five centers. The centers (and acting directors) are as follows: Center for Integrative Craniofacial Research (Acting Director, Dr. Ann Sandberg); Center for Biotechnology and Innovation (Acting Director, Dr. Eleni Kousvelari); Center for Infectious Diseases and Immunology (Acting Director, Dr. Dennis Mangan); Center for Clinical Research (Acting Director, Dr. Bruce Pihlstrom); and Center for Health Promotion and Behavioral Research (Acting Director, Dr. Dushanka V. Kleinman).
Dr. Tabak noted that a search is underway for permanent directors of two of the centers (Center for Biotechnology and Innovation, Center for Infectious Diseases and Immunology). The Division of Extramural Activities, which performs administrative functions, will remain as is.
Dr. Tabak stated that Dr. Dushanka V. Kleinman, who has been on detail to the Office of the Director, NIH, will formally return to NIDCR on September 26 as Deputy Director. He applauded Dr. Henning Birkedal-Hansen, who has been serving as Deputy Director and who will become Associate Director for Program Direction.
Two NIH Initiatives
New NIH Award. Dr. Tabak reported that NIH announced on September 8 the availability of Institutional Clinical and Translational Science Awards (CTSAs) to provide support for clinical research infrastructure at academic health centers. A Request for Applications (RFA) will be issued on October 12, and NIH will hold a meeting on October 17 to discuss the award and answer questions. The meeting will be videocast and will be archived at http://www.videocast.nih.gov. Dr. Richard L. Mowery, in the new Center for Clinical Research, is the NIDCR contact.
Sharing Credit on Research Grants. Dr. Tabak noted that NIH has been addressing the status of co-principal investigators on NIH-supported research grants. He anticipated that, in spring 2006, NIH will institute procedures to formally acknowledge and recognize multiple principal investigators on NIH grants.
Blue Ribbon Panel
In March 1993, NIDCR (then the National Institute of Dental Research) published the first NIH review of an intramural research program. Dr. Tabak noted that this successful effort led NIH to mandate intramural reviews in each NIH institute and center (IC) every 10 years. NIDCR is presently organizing its 2nd review, which will be conducted by a Blue Ribbon Panel on Planning for the Future of the Intramural Research Program. Dr. Tabak noted that the Office of the Director, NIH, has approved the review panel and plan, a notice has been published in the Federal Register, and the panel met on September 22 to draft an agenda for its review. The review meeting, which will be held at NIDCR, is scheduled for February 27–28, 2006. The panel is cochaired by Drs. Philip Stashenko and Brigid Hogan and consists of eight members who include both a former and a current Council member. Dr. Tabak said that the panel will function as an NADCRC subcommittee and will report its findings and recommendations to the NADCRC.
NIDCR has asked the panel to focus on the set of standard topics for NIH intramural reviews, as well as additional items. The standard topics include innovation and impact of research, organization of the program, effectiveness of the Board of Scientific Counselors (BSC), balance between clinical and lab-based research, funding balance between the extramural and intramural programs, space, quality of postdoctoral training, recruitment issues, and interaction with NIH officials. The three additional topics of interest to NIDCR are future scientific directions, emerging opportunities, and match between current resources (including key personnel) and current and future directions. Dr. Tabak noted that the panel will not specifically review the science conducted in the intramural program because this review is conducted by the BSC.
"Large-" vs. "Small"-Scale Science
Dr. Tabak summarized a presentation he made to the NIH leadership on the benefits of supporting small-scale science. He noted the tension between large- and small-scale science and the need to balance support between them. Over the past 4 years, NIDCR has modified its extramural research portfolio to achieve this balance and to respond to current and future challenges.
An "environmental scan" of the NIDCR portfolio in FY 2000, compared with that in FY 2004, shows that NIDCR continues to give primary emphasis to research project grants (74 percent of extramural funding in FY 2000, 78 percent in FY 2004); has reduced support for program project grants (13 percent to 5 percent) and centers (10 percent to 4 percent); consistently supports training and career development (9 percent both years); and has slightly decreased support for contracts (6 percent to 5 percent). Dr. Tabak noted that, during the 4 years, NIDCR has sought to advance clinical research—a major research challenge across NIH—by renewing emphasis on phase III clinical trials and by fostering research to reduce oral health disparities. To obtain the necessary funds and in accordance with the NIDCR Strategic Plan for 2003–2008, NIDCR instituted a moratorium on unsolicited program project grants, refocused the centers program (e.g., collaborated with the National Center for Minority Health and Health Disparities to develop more robust minority health research centers), and let existing contracts expire. Also in accordance with the strategic plan, NIDCR launched Practice-Based Research Networks (PBRNs) and worked with the dental education community to improve the quality of applications for phase-III clinical trials.
Dr. Tabak noted that these changes have enabled NIDCR to continue support for small-scale science while identifying and addressing research areas for large-scale science to focus on health priorities. NIDCR has been able to double its funding for phase-III clinical trials and is queuing up clinical trials for the next 3–5 years. NIDCR revised its procedures for clinical trials applications and is encouraging investigators to communicate directly and early with NIDCR program staff before submitting applications.
Dr. Tabak emphasized that success in science is tied to diversity in science and the balance between small- and large-scale science. He noted that most research that is truly needed can be funded and that research organizations can define and indicate which research areas they can and cannot support.
V. IMPLEMENTATION PLAN REPORT AND DISCUSSION
Dr. Birkedal-Hansen presented an update on the NIDCR Implementation Plan and elaborated on 15 major impact areas. He noted that NIDCR is very appreciative of the role and participation of Council members in developing the draft plan. Prior to the Council meeting, NIDCR forwarded a copy of the draft plan to each Council member.
Dr. Birkedal-Hansen remarked that the Implementation Plan follows closely the format of the NIDCR Strategic Plan and will guide annual planning of specific NIDCR initiatives. The Implementation Plan was developed over the past 20 months with broad input from the extramural research community, intramural research scientists, and NIH staff. The process began with staff’s internal analyses of gaps and scientific opportunities in NIDCR program areas. Subsequently, NIDCR convened 10 working groups which represented the program areas, as well as separate meetings to focus on mucosal immunity and on research training and career development. The draft Implementation Plan was posted on the NIDCR Web site on September 7, 2005. NIDCR is soliciting public comments through October 31, 2005. Staff will assess and evaluate the comments and then finalize the plan, which will be submitted to Council for approval at its January 2006 meeting.
Dr. Birkedal-Hansen emphasized that, like the NIDCR Strategic Plan, the Implementation Plan is a "living document" that NIDCR will revise and update periodically as new scientific discoveries and opportunities emerge. He noted that the plan incorporates the following three novel approaches, which were highlighted by the working groups: (i) use of technologies, genomics, proteomics, high throughput analyses, and miniaturization to move science toward systems approaches; (ii) establishment of registries, data banks, and networks [e.g., for Sjögren’s syndrome, temporomandibular joint and muscle disorders (TMJDs), PBRNs]; and (iii) realization that most craniofacial diseases are complex diseases involving genetic, molecular, environmental, and behavioral factors.
The draft plan includes approximately 144 recommendations for action. Dr. Birkedal-Hansen elaborated on 15 major impact areas and gave examples of research directions in each area. These areas and directions are as follows: (1) ORAL MICROBIOLOGY – complete an inventory of the oral microbiota; understand biofilm assembly, disassembly, communication, and quorum sensing. (2) ORAL IMMUNOLOGY – define the cells, genes, proteins, and signaling networks that constitute and regulate the oral mucosal immune system; define the protective and destructive mechanisms of mucosal and systemic immune responses. (3) CRANIOFACIAL DEVELOPMENTAL BIOLOGY AND BIOMINERALIZATION – understand the development and differentiation potential of embryonic and postnatal stem cells; define the mechanisms of biomineralization. (4) TISSUE ENGINEERING, REGENERATION, AND REPAIR – develop "smart" synthetic compounds with biomimetic properties; develop the "lab on a chip." (5) ORAL AND PHARYNGEAL CANCER – develop and validate screening technologies; define the transition from premalignant to malignant lesions. (6) OROFACIAL PAIN – develop reliable criteria for diagnosis and treatment of TMJDs and other orofacial pain conditions; understand the interplay between neurons and glial cells. (7) BIOMARKERS, NANOTECHNOLOGY – develop rational, predictive biomarkers for oral and craniofacial diseases; explore nanotechnology for diagnosis and repair of oral diseases.
(8) SALIVARY GLAND RESEARCH – identify and determine the function of all proteins secreted by salivary glands; develop gene transfer approaches to gene therapy and gene therapeutics; improve and refine salivary diagnostics; (9) CLINICAL TRIALS AND CLINICAL RESEARCH – conduct intervention trials to determine the efficacy of prevention and treatment of periodontal disease on systemic diseases identified in association studies; develop technologies to diagnose and quantify caries lesions before cavitation; (10) PHARMACOGENETICS – develop research in this emerging field to understand the pharmacogenetics of dental fluorosis; (11) BEHAVIORAL RESEARCH – explore human behaviors affected by chronic orofacial pain; incorporate reliable behavioral and social science outcome measures in dental and oral clinical research and trials. (12) HEALTH DISPARITIES RESEARCH – develop scientifically based definitions of race and ethnicity; conduct epidemiological surveys and interventions of well-defined U.S. population subgroups. (13) TRAINING – refine training opportunities proactively as the science evolves and as the needs in the extramural community change. (14) SURVEYS – stay abreast of disease developments in population groups and subgroups. (15) COMMUNICATION – transmit knowledge and skills to clinicians and the public.
Discussion
Dr. Birkedal-Hansen invited the Council's to comment on the draft Implementation Plan. The Council members stated that the draft plan is comprehensive and well-conceived, embraces the concerns and interests of all stakeholders, and will serve as a cornerstone for future directions at NIDCR. They addressed several topics as follows.
A Detailed Plan of Action. Members encouraged NIDCR to distill the "macro" plan into a detailed plan of action that specifies the "who, what, how, and when" for each goal in the plan. Drs. Tabak and Birkedal-Hansen said that NIDCR will consider this aspect, as well as mechanisms of support, within the context of NIH needs and interests. Dr. Tabak suggested that "who" will do the recommended research (extramural or intramural scientists?) may be one topic that NIDCR and Council could address jointly.
Research Areas Not Supported. The Council suggested that NIDCR may wish to make explicit in the plan which research areas will not be supported. Dr. Tabak noted that the draft plan communicates de facto which areas will not be supported. NIDCR staff noted that the plan is intentionally broad and that the research which NIDCR will support will depend in large part on the innovation and ingenuity of investigators. Dr. Birkedal-Hansen encouraged principal investigators to contact NIDCR program staff to discuss their research interests and ideas.
Recruitment of Researchers and Faculty. The Council emphasized that recruitment (and training) of individuals as researchers and dental school faculty is a continuing, overall concern. Dr. Birkedal-Hansen welcomed suggestions for addressing this problem. He noted that NIDCR proposes to fund initiatives for college students, to attract them into research careers in dentistry, and for junior dental school faculty, to provide research training at their home institution. Dr. Tabak added that NIDCR is exploring with NIH various models for giving incentives for clinical research. He anticipated that NIH would soon release a revised RFA for T90/R90 awards which would allow institutions to propose training of foreign nationals in areas of understaffed science (including dental science) in the United States.
The Council cautioned that broad programs to recruit college and high school students into science may not be feasible or effective in a time of limited resources. Rather, emphasis may be better placed on identifying individuals who are interested in science and supporting them intensively.
Dental School Curricula. The Council urged NIDCR to partner with the American Dental Education Association and the American Dental Association to steer changes in the accreditation of dental schools toward curricula that include more research and evidence-based dentistry. The members emphasized that the professional culture of dental schools, which includes dental deans' expectations, must be changed to favor dental science and research. They suggested that dental organizations could mandate and enforce curricula that include evidence-based dentistry and that every dental school could be challenged to commit 10 percent of its entering students to an honors program that includes research.
Dr. Tabak noted that NIDCR cannot "do the lifting" alone and that all partners must join in direct efforts to change dental school curricula. He suggested that the time may be ripe now because of an unprecedented spirit of collaboration and cooperation that currently exists among the dental professional organizations and because of the active engagement of the Council on this issue. Dr. Birkedal-Hansen noted that NIDCR encourages the incorporation of research and science methodology into the curriculum of every dental school. NIDCR welcomes Council's suggestions on how NIDCR could "drive" the effort.
Dissemination of Knowledge to Practitioners and the Public. The Council noted that the transmission of skills and knowledge to practitioners (e.g., on the use of sealants), as well as dental schools, is a complex undertaking. The Council suggested that dental schools have an important role in improving the health literacy of the public and that the training of dental students should include encouragement of them to serve as public health educators. For example, within dental school curricula, students could be encouraged, as future clinicians, to demonstrate the evidence for a treatment and to impart this knowledge to their patients and the public. The Council commented that the professional demands of using scientific knowledge to treat patients and of communicating knowledge to patients and the public are common to both dentistry and medicine and that dentistry could be a leader in enhancing the relationship between practitioners and the public.
Dr. Tabak thanked the Council for its very rich discussion of significant issues.
VI. CONCEPT CLEARANCE
NIDCR staff presented six concepts for Council's approval. For each concept, two Council members served as leads and presented in-depth reviews for the Council’s discussion. Staff provided written, detailed concepts to each Council member.
Nanostructured Dental Composite Restorative Materials
Dr. Rosemarie Hunziker, Director, Technology Development and Industrial Relations Program, Center for Biotechnology and Innovation (CBI), presented a proposed RFA to encourage nanotechnology and nanoscience approaches in the design and development of composites to improve existing dental restorations. Dr. Hunziker noted that clinicians have used composites for many years, yet major issues remain. Three key challenges are shrinkage stress, which leads to failure at the margins; long-term durability under mastication, which is far from optimal; and tooth-like aesthetics, which is often compromised to obtain strength and durability. Recent advances in nanotechnology make it possible to address some of these issues. For example, scientists can use nanofibers and nanorods to reinforce a composite; nanosphere-based fillers to increase the surface area and contact; monomers that expand to counteract shrinkage stresses; and nanoparticles that present surfaces that closely mimic the dimensions of a natural tooth.
With this initiative, NIDCR aims to address the underlying nanoscience in order to gain a mechanistic understanding of nanostructured dental composites. The research would be focused on significant knowledge gaps, which include understanding the underlying chemistries to improve the bonding of interfaces, deciphering the three-dimensional structure of the basic building blocks of a composite and its interface with the tooth structure, and assessing the biocompatibility of new materials that are developed. The expected outcomes are new formulations with improved properties for dental composites, increased understanding of the underlying science, and better design processes.
The Council leads commented that NIDCR has led the introduction of the latest advances in materials sciences into medicine and health care for a long time. They noted that the concept addresses very difficult challenges, yet realistic goals, in materials sciences; captures the frontiers of materials sciences and nanotechnology; would attract nondental researchers into pursuing dental applications; and accords with the NIDCR Strategic Plan. They also noted that NIDCR supports more than two dozen projects in dental composite restorations, of which seven include research on nanobased composites. The leads encouraged NIDCR to (i) assure that the research to be supported under the concept is not redundant with studies that NIDCR already supports and (ii) modify the title of the concept to reflect a broader focus on the frontiers of materials sciences (which includes nanotechnology).
The Council unanimously approved the concept.
New Models of Trigeminal Pain for Basic, Translational, and Clinical Research
Dr. John W. Kusiak, Health Scientist Administrator and Program Director, Molecular and Cellular Neurobiology Program, Division of Basic and Translational Sciences (DBTS), presented a concept to stimulate research that will lead to (i) development and validation of animal models of chronic human pain disorders that better represent current knowledge of the human pain condition and (ii) development of human models to study chronic pain that include innovative and noninvasive objective measures of pain in humans. Dr. Kusiak noted that successes in treating experimental pain in animal studies in the laboratory have not always been followed by successful therapeutic outcomes in clinical trials. From a research perspective, this lack of translation suggests that scientists do not fully understand the targets or pathways involved in chronic pain. Clinically, effective therapies for treating chronic pain are lacking and are urgently needed. Better informed translational research is needed because the usual models and measures of pain from basic studies in animals may not be the most reliable and valid measures of clinical pain.
The initiative would encourage a translational research approach to define the best experimental models and measures of human pain and of animal pain that reflects chronic pain states in humans and to help speed the development of new treatments for these conditions. The primary expected outcomes are pain researchers' use of more effective translational approaches, leading to more rapid identification and validation of new targets for treatment, and, ultimately, development of new and improved therapies for chronic pain.
The Council leads agreed that existing animal models are not sufficient for understanding human pain and that new models that mimic clinical states of chronic pain are needed. They agreed that the concept is limited and not particularly novel and may not stimulate new approaches. The leads suggested that NIDCR redraft the concept to focus on the modeling of specific pain conditions and diseases, as well as measures of human pain, or incorporate the concept into another initiative.
The Council did not approve the concept. The Council approved a motion to consider revising the concept to focus on specific chronic orofacial pain conditions for which particular models, measures, and mechanisms would be applied.
TMJDs—Pathophysiological Mechanisms Linking Comorbid Conditions
Dr. John W. Kusiak presented a concept to stimulate collaborative research on discovering the biological mechanisms underlying the etiology and pathophysiology of a set of chronic conditions associated with TMJDs. He noted that TMJD is a complex and heterogeneous disease that likely represents a collection of disorders of varying etiology and is difficult to treat. Further complicating the treatment are other chronic illnesses that are sometimes associated with TMJDs (e.g., fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, multiple chemical sensitivity, hearing and speech disorders, certain cardiovascular diseases), as well as other craniofacial disorders (e.g., migraine headache, trigeminal neuralgia, atypical face pain). Dr. Kusiak noted that the etiological and pathophysiological mechanisms linking TMJDs and these comorbid conditions are unclear and are likely to represent abnormalities in the responses and interactions of common homeostatic mechanisms. He also noted that the increased prevalence of TMJDs in women indicates that sex hormones play an important and complex role.
Dr. Kusiak noted that the initiative would stimulate collaborations among researchers with an interest in TMJDs and with specific expertise in research areas related to the overlapping comorbid conditions. The initiative, which is being developed as a collaborative effort by the Temporomandibular Joint Disorders Interagency Working Group, also would stimulate cross-NIH programmatic collaborations. The expected outcomes are (i) a better understanding of how TMJDs and comorbid conditions interact to influence the development, course, and persistence of TMJDs and (ii) a better understanding of the etiology of TMJDs.
The Council leads remarked that the concept is exciting and well-conceived and presents a rational approach to the study of TMJDs and comorbid conditions—an enigmatic set of clinical entities. They noted that the collaborative approach proposed is novel and insightful. The leads suggested that the concept could be broadened further to include research on other orofacial pain syndromes and on the linkage of TMJDs and these syndromes with infectious diseases and metabolic diseases. NIDCR staff commented that the list of comorbid diseases presented in the concept does not exclude research on other diseases and conditions. A Council member cautioned against trying to study TMJD as an overall experimental outcome and suggested that studies focus on specific symptoms of TMJD.
The Council approved the concept.
Ontogeny of Host Innate Immune Recognition of and Response to Oral Microbes
Dr. Sangeeta Bhargava, Health Scientist Administrator and Program Director, Immunology and Immunotherapy Program, DBTS, presented a concept to stimulate research that will address, at a molecular and cellular level, the ontogeny (i.e., age-related development) of the recognition of and response to oral microbes by the oral innate immune system. Dr. Bhargava noted that oral microflora consist of bacteria, viruses, fungi, and parasites and that most of these microflora are commensals (normal flora) coexisting within the oral cavity without causing disease. She noted further that this harmonious interplay is due to a dynamic molecular cross-talk between the microflora and the host and the capacity of the innate immune system to recognize most of the microbes as non-harmful. How this innate immune system—an ancient evolutionary response—accomplishes this recognition and response is unknown.
The initiative would specifically solicit research to define how the host, beginning at birth, distinguishes between commensal and pathogenic microbes. Investigators would be encouraged to (i) study the molecules on oral microbes that are recognized by the innate immune system; (ii) determine how a host recognizes the molecules on the microbes and how a host’s recognition changes with age; (iii) delineate the ontogeny of salivary components related to innate immunity; and (iv) study the ontogeny of molecular mechanisms by which an innate immune system responds to oral microbes; the possible individual host genetic differences in innate immunity to oral microbes; and the connection between a host’s innate and acquired immune systems.
Dr. Bhargava noted that the initiative is feasible because of the relatively easy access to oral mucosa and saliva; the availability of good animal models for studying oral innate immunity; and the availability of bioinformatics, genomics, proteomics, and state-of-art technologies for tissue analyses. A goal is to build upon the knowledge that is being gained from studies of innate immunity and responses to intestinal microbes and to encourage these researchers and other investigators to focus on cellular and molecular mechanisms involved in the ontogeny of oral innate immunity.
The Council leads expressed great enthusiasm for the concept. They agreed that the proposed initiative is very timely and thoughtful, identifies a number of important issues that are feasible to address now or shortly, addresses major gaps in knowledge, and fits well within the NIDCR Strategic Plan. They noted that the oral cavity and the oral innate system confront 90 percent of all pathogens that humans experience in a lifetime. The leads suggested that NIDCR edit the concept to more clearly frame the initiative within the context of ontogeny—the development from birth, and even embryologically, to senescence.
The Council unanimously approved the concept.
Pharmacogenetics of Fluoride
Dr. Lillian Shum, Health Scientist Administrator and Program Director, Physiology, Pharmacogenetics, and Injury Program, DBTS, presented a concept to stimulate research on the genetic basis underlying individual responses to ingested fluoride. She noted that, over the past 50 years, scientists have accumulated knowledge about the effects of fluoride on both mineralized and non-mineralized tissues and that these studies indicate that the extent of the effectiveness of fluoride on mineralized tissues of teeth and on other physiological systems varies greatly among individuals. Further, human and animal studies suggest that genetic factors may contribute to the range of effects, but the genetic determinants of individuals' physiological responses to fluoride have not been explored. The concepts and approaches used in pharmacogenetics could be useful in this regard. Dr. Shum noted that pharmacogenetics—the interdisciplinary study of how genetic variations determine heterogeneous responses to chemical compounds—is at the forefront of the progress being made in genetics and genomics.
The initiative would encourage studies to identify and describe the function of genes and genetic polymorphisms in fluoride-sensitive genes, gene–gene and gene–environment interactions that modify the function of genetic variants, and development and validation of predictive biomarkers of the fluoride response. The knowledge gained would serve as a basis for individualized recommendations of total fluoride intake and would enhance knowledge of the fundamental mechanisms by which fluoride influences biomineralization.
The first Council lead commented that the proposed initiative is well-conceived and well-planned. She noted that, as an example of small-scale science taking advantage of advances in large-scale science, the research could build on knowledge gained from studies of animal models to identify and validate the pharmacogenetics of fluoride (e.g., among different ethnic groups).
The second Council lead noted that seeking a new understanding of fluoride exposure and individuals' responses to fluoride is important and consistent with the NIDCR mission. The lead expressed concern, however, about the breadth of the initiative and the range of studies being encouraged. He noted three particular concerns: (i) the need for careful selection of animal models regarding their predictive relevance, especially with respect to pharmacogenetics and gene toxicity; (ii) the need to narrow the scope of the concept to ensure targeted outcomes against the most important questions and to prioritize research areas; and (iii) the need to consider potential outcome scenarios and to use common, meaningful research standards so that the significance and findings of the research are broadly understandable and applicable.
The Council lead emphasized the need to address the question "what is the relevance of the data?" before funding the science, to consider practical questions upfront, and to require that each research design includes agreed-upon benchmarks or standards to help clarify outcomes. He noted that the key challenge of the research would be to define which responses are fluoride-specific, adaptive, protective, or unrelated to fluoride exposure. He encouraged NIDCR to give consideration upfront to potential study designs, the experimental agenda, gene-profiling standards, and appropriately framed questions. He emphasized that the research should not be ad hoc and that study sections would need guidance for their review of proposals. The lead further urged NIDCR to "mine" data from existing literature to establish relevant dosing ranges for both animal and in vitro study assays; to establish benchmark controls for dosing studies and to define known and accepted genetic standards and standard genomic and proteomic methods in the eventual RFA; and to consult in advance with experts in the assessment of public health risks of toxico-genomic issues.
Dr. Tabak thanked the leads and noted that their comments on this new area of research for NIDCR were very helpful. In discussion, Council members encouraged NIDCR to explicitly include in the concept (a) epigenetic studies and (b) basic research to better understand the mechanisms of action of fluoride.
The Council motioned that the concept be approved "with appropriate attention being paid to creating and explicitly defining the construct in advance (e.g., genetic standards, dosing ranges/regimens, standardized methods, and biometric expectations) consistent with the broader genomic knowledge base, leveraging the known science related to fluoride to date, and ensuring that all proposals are responsive to these parameters."
The Council unanimously approved the concept as modified.
Effects of Long-Term use of Antiretroviral Therapy (ART) on the Oral Mucosa
Dr. Mostafa Nokta, Health Scientist Administrator and Program Director, AIDS and Oral Manifestations of Immunosuppression Program, DBTS, presented a concept to study the effects of long-term use of ART on oral mucosa tissues. He noted that the life expectancy of patients with HIV/AIDS has improved significantly over the past 10 years, in part because of the advent of multiple classes of ARTs and better understanding of the management of medical complications of HIV/AIDS. The survival of patients, however, is dependent on continuous treatment with ART. Although ART has many beneficial effects, clinicians have reported an association between ART and certain oral disorders, including plasmoblastic lymphomas of the lower jaw and benign human papillomavirus-associated lesions of the oral cavity, such as papillomas, chondylomas, and focal epithelial hyperplasia. Moreover, clinicians have noted that certain ART regimens are associated with impairment of exocrine glands, a finding that suggests that ART may be associated with impairment of salivary gland function. In addition, researchers have observed that ART has toxic effects on lymphocytes and on liver, muscle, and fat cells.
Dr. Nokta emphasized that the effects of long-term ART on oral mucosal tissues have not been studied. The purpose of the initiative would be to encourage research that would utilize cellular and molecular high throughput technology to study the effects of ART exposure—for example, on differentiation, function, and physiology of oral mucosal cells; on innate and adaptive oral mucosa immunity; on salivary gland function; and on transmission of microbes into and out of oral mucosal tissues. The studies could be conducted on ex-vivo organotypic models of the human oral mucosa, simian models for AIDS, and tissues from patients receiving ART. The expected outcomes are insights on oral mucosal disorders that may be associated with long-term use of ART and strategies for reducing the negative effects of these threats.
The Council leads agreed that the proposed initiative is very timely, well-conceived, clinically relevant, and desperately needed. They noted that oral lesions in patients receiving highly-active ART (HAART) may be a sentinel of change in the susceptibility of patients to HAART or some underlying condition in the patients that could limit the long-term effectiveness of this therapy. Establishing why oral lesions occur is therefore highly important. One lead suggested that NIDCR encourage collaborations among researchers studying the different tissues (ex-vivo, simian, and patients') and use of the same technologies having the same sensitivity for all sources of tissues.
The Council unanimously approved the concept.
VII. 2005 NIDCR SEYMOUR J. KRESHOVER LECTURE
The 2005 NIDCR Seymour J. Kreshover Lecture took place after the Council meeting. This lecture, to honor a former director of NIDCR, was given in the Lipsett Amphitheater in Building 10, NIH. The speaker was Dr. Charles N. Serhan, Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, and Simon Gelman Professor of Anesthesia, Harvard Medical School, Boston, Massachusetts. His lecture was entitled "The Role of Novel Anti-Inflammatory and Pro-Resolving Lipid Mediators in Oral Inflammation and Resolution."
Dr. Serhan is known internationally for his research on the mechanisms of inflammation and the biochemistry of blood cells. He has discovered that the "resolution" of acute inflammation in mice is an active, self-limiting process and can be treated by compounds (resolvins) that trigger cellular and biochemical responses, rather than by compounds that strictly inhibit inflammation. In conversations with NIDCR staff during the 1990s, he became interested in the clinical implications of his findings for periodontal disease. Supported by a program project grant from NIDCR, he and his colleagues are accelerating research on endogenous mediators of inflammation that protect against the bone destruction that arises with periodontitis.
CLOSED PORTION OF THE MEETING
This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).
There was a discussion of procedures and policies regarding voting and confidentiality of application materials, committee discussions, and recommendations. Members absented themselves from the meeting during discussion of and voting on applications from their own institutions, or other applications in which there was a potential conflict of interest, real or apparent. Members were asked to sign a statement to this effect.
VIII. REVIEW OF APPLICATIONS
Grant Review
The Council considered 426 applications requesting $85,699,134 in total costs. The Council recommended 330 applications for a total cost of $64,735,382 (see Attachment II).
ADJOURNMENT
The meeting was adjourned at 3:00 p.m. on September 23, 2005.
CERTIFICATION
I hereby certify that the foregoing minutes are accurate and complete.
________________________ _________________________
Dr. Lawrence A. Tabak Dr. Norman S. Braveman
Chairperson Executive Secretary
National Advisory Dental and National Advisory Dental and
Craniofacial Research Council Craniofacial Research Council
ATTACHMENTS
I. Roster of Council Members
II. Table of Council Actions
III. Director’s Report to the NADCRC, September 2005
NOTE: A complete set of open-portion handouts is available from the Executive Secretary.