Date: September 18, 2006
Place: Building 31, Conference Room 10
National Institutes of Health
Bethesda, Maryland
U.S. DEPARTMENT OF HEALTH
AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
The 183rd meeting of the National Advisory Dental and Craniofacial Research Council (NADCRC) was convened on September 18, 2006, at 8:40 a.m., in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. The meeting was open to the public from 8:40 a.m. to 12:45 p.m. followed by the closed session for Council business and consideration of grant applications from 1:15 p.m. until adjournment at 3:00 p.m. Dr. Lawrence A. Tabak presided as Chair.
Members Present:
Dr. Matthew J. Doyle
Dr. Marianne Bronner-Fraser
Dr. Eli Capilouto
Dr. Cecile Feldman
Dr. Linda G. Griffith
Dr. Mark C. Herzberg
Dr. Josephine Lai
Dr. Jon D. Levine
Dr. Anne S. Lindblad
Dr. Harold Morris
Dr. Michael Reed
Dr. Philip Stashenko
Dr. George Taylor
Members of the Public Present:
Ms. Molly J. Buehn, Project Director, Social Scientific Systems, Inc., Silver Spring, MD
Dr. Aida A. Chohayeb, Women Network Collective Research, Washington, DC
Dr. Frank A. Kyle, Jr., Manager, Legislative and Regulatory Policy, American Dental Association, Washington, DC
Ms. Allison Trepod, Research Analyst, SRI International, Rosslyn, VA
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. Jane Atkinson, Program Director, Clinical Trials Program, Center for Clinical Research (CCR)
Dr. Albert Avila, Extramural Training Officer, Office of the Director (OD)
Dr. Sangeeta Bhargava, Program Director, Immunology and Immunotherapy Program, Center for Integrative Biology and Infectious Diseases (CIBID)
Dr. Henning Birkedal-Hansen, Associate Director for Program Development, NIDCR
Dr. Norman S. Braveman, Executive Secretary, NADCRC, and NIDCR Board of Scientific Counselors, and Assistant to the Director, OD
Dr. Patricia A. Bryant, Program Director, Basic and Applied Behavioral/Social Science Research Program, Center for Health Promotion and Behavioral Research (CHPBR)
Dr. María Teresa Canto, Program Director, Health Promotion and Community-Based Research Program, CHPBR
Dr. John A. Chiorini, Tenured Investigator, Adeno-Associated Virus Biology Unit, Gene Therapy and Therapeutics Branch, DIR
Mr. George J. Coy, Chief, Financial Management Branch (FMB), Office of Administrative Management (OAM)
Mr. Kevin L. Crist, Grants Management Specialist, Grants Management Branch (GMB), Division of Extramural Activities (DEA)
Ms. Mary Daley, Chief Grants Management Officer, GMB, DEA
Mr. Bret Dean, Budget Analyst, FMB, OAM
Dr. Isabel Garcia, Acting Director, Office of Science Policy and Analysis (OSPA), and Co-Director, Residency Program in Dental Public Health at NIDCR
Ms. Christen Geiler, Computer Specialist, Office of Information Technology (OIT), OD
Dr. Kevin Hardwick, Extramural Training Officer, NIDCR
Dr. Rosemarie Hunziker, Program Director, Technology Development and Industrial Relations Program, Center for Biotechnology and Innovation (CBI)
Ms. Mary Kelly, Scientific Review Specialist, Scientific Review Branch (SRB), DEA
Ms. Sooyoun Kim, Scientific Review Specialist, SRB, DEA
Dr. Lynn M. King, Scientific Review Administrator, Scientific Review Branch (SRB), DEA
Dr. Dushanka V. Kleinman, Deputy Director, NIDCR, and Acting Director, CHPBR
Dr. Eleni Kousvelari, Acting Director, CBI
Dr. John W. Kusiak, Director, Molecular and Cellular Neuroscience Program, CIBID
Dr. Yujing Liu, Scientific Review Administrator, SRB, DEA
Ms. Carol Loose, Budget Analyst, FMB, OAM
Dr. Nadya Lumelsky, Program Director, Tissue Engineering and Regenerative Dental Medicine Program, CBI
Mrs. Jayne Lura-Brown, Program Analyst, CHPBR
Dr. Pamela McInnes, Director, CIBID
Dr. Mostafa Nokta, Program Director, AIDS and Immunosuppression Program, CIBID
Dr. Ruth Nowjack-Raymer, Program Director, Health Disparities Research Program, CCR
Dr. Bruce Pihlstrom, Acting Director, CCR, and Program Director, Clinical Trials Program, CCR
Dr. Yasaman Shirazi, Program Director, Epithelial Cell Regulation and Transformation Program, CIBID
Dr. Lillian Shum, Program Director, Mineralized Tissue and Salivary Gland Physiology Program, CIBID
Dr. Rochelle Small, Program Director, Developmental Biology and Genetics Program, CIBID
Ms. Ruth Dianne Thorpe, Administrative Officer, OAM
Ms. Traci Walker, Committee Management Assistant, OD
Ms. Anne Welkener, Financial Analyst, DEA
Other Federal Employees:
Dr. Mary Frances Deutsch, Assistant Grants Compliance Officer, Division of Grants Compliance and Oversight, Office of Policy for Extramural Research Administration, Office of Extramural Research, Office of the Director (OD), NIH
Dr. Michael M. Gottesman, Deputy Director for Intramural Research, OD, NIH
Dr. Raynard S. Kington, Deputy Director, OD, NIH
Dr. William Maas, Director, Division of Oral Health, Centers for Disease Prevention and Control, Chamblee, GA
Dr. Ravi K. Sawhney, Office of Science Policy and Planning, Office of Science Planning, OD, NIH
OPEN PORTION OF THE MEETING
I. WELCOME AND INTRODUCTIONS
Dr. Lawrence A. Tabak, Director, NIDCR, called the meeting to order and welcomed everyone. He asked the Council members and guests to introduce themselves. Dr. Tabak noted that three Council members had completed their respective tenures on the Council: Drs. Linda Griffith, Mark Herzberg, and Michael Reed. He thanked them individually for their contributions to the Council and presented each with a certificate of appreciation.
Dr. Norman S. Braveman, Executive Secretary, NADCRC, noted that, for the first time, the Council meeting was totally electronic, in that each Council member was given a laptop computer by NIDCR to use during the meeting to access informational items for the meeting.
II. APPROVAL OF MINUTES
The minutes of the Council’s meeting on May 22, 2006, were considered and unanimously approved.
III. FUTURE COUNCIL MEETING DATES
The following dates for future Council meetings were confirmed:
January 22, 2007
May 18, 2007
September 24, 2007
January 25, 2008
June 6, 2008
September 26, 2008
IV. REPORT OF THE DIRECTOR, NIDCR
Dr. Tabak highlighted several items from the written Report of the Director, which was provided to the Council (see Attachment III) and is available on the NIDCR website (www.nidcr.nih.gov). Additional details and items are in the written report.
Research Results for the Public
Dr. Tabak encouraged the Council to peruse and use information and fact sheets from the new NIH website Research Results for the Public (www.nih.gov/about/researchresultsforthepublic/). The site includes, for example, information on periodontal diseases and tooth decay.
Symposium Honoring Dr. Lois K. Cohen
A symposium honoring Dr. Lois K. Cohen, former Associate Director for International Health, NIDCR, will be held at NIH on December 11, 2006, in the Lipsett Amphitheater, Building 10, from 8:30 a.m. to 12:00 noon. The symposium is entitled “The Integral Role of Behavioral and Social Sciences in a Systems Approach to Oral Health Research: A Tribute to Dr. Lois K. Cohen.”
TMJ Disorders Patient Brochure Now Available
Dr. Tabak reported that NIDCR recently released a revised patient education brochure on temporomandibular joint and muscle disorders (TMJD). The brochure, which is entitled “TMJ Disorders,” should be of great benefit to TMJ patients. It can be viewed on the NIDCR website, and printed copies will be available at the end of September.
NIDCR Personnel
Dr. Bruce Pihlstrom, Acting Director, Center for Clinical Research (CCR), NIDCR, introduced Dr. Jane Atkinson, who will manage day-to-day activities of the Clinical Trials Program. Formerly, Dr. Atkinson was deputy clinical director in the NIDCR intramural program.
Dr. Tabak reported that Ms. Yvonne duBuy, Associate Director for Management, and Director, Office of Administrative Management (OAM), NIDCR, retired from Federal service on September 1 after 37 years with the Federal Government and 18 years at NIDCR. Ms. duBuy will continue to assist NIDCR as a contractor. Mr. Thomas G. Murphy is serving as Acting Executive Officer, OAM.
Dr. Tabak also noted that Dr. Karl A. Piez, NIDCR scientist emeritus, passed away on August 25. Working in the intramural laboratories for 30 years, Dr. Piez advanced understanding of the structure and mechanisms involved in the cross-linking of collagen.
V. CONCEPT CLEARANCES
Dr. Braveman introduced the presentation of five concept clearances for Council’s approval. Following each presentation by NIDCR staff, two Council members served as leads for the discussion and presented in-depth reviews of the concept. NIDCR provided detailed, written concepts to the Council members in advance of the meeting.
Osteoimmunology: Cross Talk between Immune System and Bone
Dr. Sangeeta Bhargava, Program Director, Immunology and Immunotherapy Program, Center for Integrative Biology and Infectious Diseases (CIBID), presented an initiative to solicit innovative research projects that would yield a fundamental understanding of the intersystem cross talk between alveolar bone and the immune system and of the operation of osteoimmunology in normal and pathological conditions. Such research would contribute to an understanding of the regulation of both systems in a physiological context at the molecular, cellular, and organ levels. Dr. Bhargava noted that most of the 700 species of bacteria that constitute the oral microbial environment are commensal and coexist without negatively affecting the oral bone.
Over the years, studies have focused on various aspects of the oral bone and have led to a good understanding of many of the key cellular and molecular mechanisms governing homeostasis of bone. However, a detailed understanding of the extensive cross talk between the oral bone and the immune system and the biological implications of these interactions are poorly understood. The gaps in knowledge include, for example, immunopathological mechanisms linking periodontal and pulpal infection and bone resorption; role of innate and adaptive immune cells, cytokines and other cellular factors, and circulating lymphocytes in normal and pathological conditions; differences in osteoimmunology cross talk in oral bone versus axial or appendicular bone; ontogeny of osteoimmune interactions in the host; and therapeutic strategies to prevent inflammation-induced bone loss.
The Council lead reviewers strongly supported the proposed initiative. They noted that it is well-conceived, worthwhile, and both focused and broad enough to stimulate exciting research on cross talk. They suggested inclusion of two additional knowledge gaps: the impinging of the neural system on both skeletal and immune function, and differences in periodontal bone resorption in cases of acute versus chronic inflammation.
The Council unanimously approved the concept.
Systems Approach to Salivary Gland Biology
Dr. Lillian Shum, Program Director, Mineralized Tissue and Salivary Gland Physiology Program, CIBID, presented an initiative to stimulate innovative research in applying a systems biology approach to understand and predict salivary gland functions, dysfunctions, and responses to treatment of salivary gland disorders. Dr. Shum commented that understanding the daunting complexity of biological systems is one of the major challenges in science today. With respect to salivary glands, researchers have collected over many years massive amounts of data on salivary gland biology. Dr. Shum noted that although these data are important building blocks (e.g., for understanding calcium signaling, ion transport, catalogs of the salivary proteome), the continued collection of data points would yield only incremental increases to the knowledge base. And, despite the mass of data accumulated, a major knowledge gap is the lack of predictive value of disconnected data points for clinical applications, such as predicting the onset and progression of salivary gland disorders.
Dr. Shum suggested that it is timely to take salivary gland research to a new level of analysis and integration by adopting a systems biology approach. She noted that this step would represent a quantum change for the field. Systems biology is an emerging inter-discipline that couples experimentation with quantitation to gain an understanding of, for example, the structure, dynamics, and regulation, and design of salivary glands. The NIDCR anticipates that the proposed initiative would facilitate productive collaborations between experimental scientists and quantitative scientists and attract quantitative scientists to careers in salivary systems biology. Dr. Shum noted that NIDCR is promoting salivary gland research as pilot studies of systems biology for other exocrine glands and will encourage collaborations between experimental researchers and the NIH Roadmap-supported National Centers for Biomedical Computing.
The Council lead reviewers strongly supported the proposed initiative. They remarked that it is timely, ambitious, forward looking, and well-articulated. They noted that it would build on other NIDCR research on salivary glands and be attractive to other NIH researchers studying basic biology (e.g., branching morphogenesis in the lung). They noted further that the salivary gland is an excellent choice for linking experimental biology with quantitative science and for linking basic research to specific clinical problems.
The Council unanimously approved the concept.
Translational Application of Gene Silencing to Oral and Craniofacial Diseases and Disorders
Dr. Rochelle Small, Program Director, Developmental Biology and Genetics Program, CIBID, presented an initiative to encourage applications that utilize gene silencing by RNA interference (RNAi) and are focused on treatment and prevention of oral and craniofacial diseases and disorders. Gene silencing by RNAi takes advantage of an endogenous defense mechanism for protecting cells from invading viruses and transposable genetic elements. Dr. Small noted that, since the first description of this capability in the mid-1990s, RNAi has emerged as a powerful, simple, highly specific, and cost-effective strategy for silencing genes. The potential therapeutic applications of RNAi are very broad, ranging from acquired diseases (e.g., viral diseases) to genetic disorders and including most areas of the NIDCR mission (e.g., bone disorders, oral cancer, chronic inflammatory conditions, viral infections, autoimmune disorders, and craniofacial birth defects).
Dr. Small noted that effective in vivo delivery of small interfering RNAs (siRNAs) to mammalian cells has been problematic, with the notable exception of mucosal surfaces, which offer easy accessibility. Three Phase I clinical studies of siRNA, all involving mucosal surfaces (i.e., the retina, respiratory tract, vagina/cervix), have been successful, and the results indicate that mucosal surfaces are an effective port of entry for topically applied siRNAs. Examples of research that would be appropriate for the proposed initiative include the silencing of inflammatory mediators causing bone erosion in periodontal diseases, silencing of immunological and pro-apoptotic factors leading to Sjögren’s syndrome, identification and validation of drug targets for head and neck cancers, and treatment of neuropathic pain.
The Council lead reviewers strongly supported the proposed initiative. They commented that the concept is timely, well-conceived, and succinctly written. The Council members suggested that NIDCR consider (i) funding the research under various mechanisms, including the R01; (ii) broadening the concept to include further development, as well as application, of the evolving technology in oral biology; (iii) noting the limitations of RNAi other than delivery; and (iv) clarifying that the initiative relates broadly to craniofacial diseases and disorders. The Council encouraged NIDCR to consider a multiyear issuance of this initiative.
The Council unanimously approved the concept.
Oral Mucosal Vaccination against HIV Infection
Dr. Mostafa Nokta, Program Director, AIDS and Immunosuppression Program, CIBID, presented an initiative to encourage research on the harnessing of mucosal immune responses for the development of effective HIV vaccines delivered via inoculation in oropharyngeal mucosal tissues. Dr. Nokta noted that, despite the resources and extensive efforts devoted to development of a protective vaccine against AIDS, major challenges still exist pertaining to vaccine design and immunization regimens. Largely relying on parenteral delivery of vaccine antigens, scientists have evaluated several investigational vaccines in clinical trials, but have been unable to demonstrate their efficacy.
Dr. Nokta noted that delivery of HIV vaccines via the oral mucosa, to achieve local and systemic protection against HIV infection, is a largely unexplored area of research. While parenteral immunization with non-replicating antigens induces mostly systemic immune responses, mucosal delivery of antigens can trigger both mucosal and systemic immune responses—as researchers have shown using intranasal, rectal, and intraoral delivery of antigens for HIV and other human viruses.
Dr. Nokta urged that the innate immune system, the first line of defense against pathogens, merits further attention in its role in preventing HIV infection and that the interaction of this system with immunologic memory and cytokines can be exploited to develop a prophylactic oral mucosal vaccine. Examples of research topics that this initiative may address include development of broadly reactive antibodies to primary isolates at oral and other mucosal sites of infection, harnessing of innate and regulatory responses in the development of oral mucosal vaccines, design of methodologies to increase and mobilize antigen-presenting cells to mucosal vaccination sites, development and validation of adjuvants to improve immunogenicity, and comparison of HIV systemic and oral mucosal responses.
The Council lead reviewers noted that the proposed initiative is important, embraces laudable scientific goals, and offers a good opportunity for NIDCR scientists to link with the larger HIV/AIDS research community. They encouraged NIDCR to modify the concept by (i) specifying the gaps in knowledge, (ii) relating these gaps to the text in the last paragraph of the “Background” section of the written concept, (iii) relating the gaps to lessons learned from other IC-supported research on mucosal vaccines (e.g., for influenza), and (iv) stating the funding mechanism to be used.
In broad discussion, the Council members also encouraged NIDCR to (i) develop further the conceptual aspects of the initiative, (ii) convey the unique opportunities in HIV vaccine development for research in the oral cavity, and (iii) focus the concept on delivery of known oral antigens in the oral mucosa, rather than antigen discovery.
The Council unanimously approved the concept within the limits of the provisos specified in the discussion.
NIDCR Scholars Program
Dr. Kevin Hardwick, Extramural Training Officer, NIDCR, presented an initiative to establish an NIDCR Oral Health Education Scholars Program. The goal is to encourage more dental students to pursue academic research careers, as a way of helping to decrease the number of faculty vacancies in dental school and to ensure a viable dental research work force. Specifically, NIDCR would invite applications from dental schools to develop D.D.S./M.S. programs for recruiting and training dentists to pursue academic research careers. Dr. Hardwick noted that, according to the American Dental Education Association, there were 250 vacant full-time faculty positions in dental school in 2004–05, and 51 (or 20 percent) of these were in research, either basic science or behavioral science. In addition, there is a shortage of new dentists entering careers in academic research.
Dr. Hardwick noted that the initiative arose from Council’s discussions and recommendation to NIDCR to develop an oral health scholars program that would promote research training and enhance the academic curricula for a subset of dental students. He noted further that this recommendation, which was publicized in the Journal of Dental Research, has stimulated much thoughtful discussion in dental schools. Dr. Hardwick thanked the Council for its discussions, recommendation, and communication of this issue.
The proposed NIDCR program would enable up to 20 percent of the students in each class to be engaged in research for at least 20 percent of their time in dental school. These scholar students would extend their time in dental school to 5 years in order to earn a master’s degree in addition to their D.D.S. or D.M.D. degree. The master’s degree program must be rigorous, integrated into the school and/or academic health center, and prepare the trainees to engage in biomedical or behavioral research. Dr. Hardwick noted that master’s degrees awarded for clinical specialty training would not be allowable as part of this program.
The Council lead reviewers fully supported the proposed initiative as a first and important step, consistent with the NIDCR Strategic Plan, for addressing a critical gap in the oral health research work force. They urged NIDCR to give appropriate weight and consideration to three principles when writing the announcement. Specifically, applicant institutions should have (i) a bona fide and demonstrated commitment to a scholars program (as detailed by NIDCR); (ii) openness to a variety of potential research endeavors (e.g., tissue engineering, pharmacoeconomics, science journalism); and (iii) a commitment to diversity and selection of women and underrepresented minority candidates.
The Council suggested that (i) NIDCR incorporate language specifying that the program would yield a terminal degree based on a research experience (e.g., an M.P.H. program may or may not include research), (ii) add a statement describing the career path for becoming an independent or collaborative researcher, and (iii) include examples of the types of research activities in a robust program. The Council members viewed the scholars program as a stepping stone for students interested in developing a research career. They commented on various career pathways and issues. Members emphasized the essential need for postdoctoral training and the value of master’s degree programs, which may have intangible “halo” effects stimulating students to pursue a Ph.D. The members also commented on the importance of research mentors and collaborative research involvement, the possibility of combining the scholars program with a clinical specialty program, and the potential opportunity of attracting postdoctoral researchers into a master’s program in dentistry.
The Council unanimously approved the concept within the limits of the provisos specified in the discussion.
VI. THE OFFICE OF PLANNING AND STRATEGIC INITIATIVES
Dr. Raynard S. Kington, Deputy Director, NIH, described the role, function, and structure of NIH’s new Office of Planning and Strategic Initiatives (OPASI) and commented on the NIH process of funding new scientific initiatives. He presented OPASI as the solution to the problem of ad hoc trans-NIH strategic planning. Dr. Kington noted that although priority setting (strategic planning) works well at each of the 27 NIH institutes and centers (ICs), it has not been effective for trans-NIH research across the ICs.
The OPASI will serve to institutionalize the trans-NIH strategic planning process (including NIH Roadmap activities) and link this process with a stream of funding (the Common Fund) to support research initiatives requiring a trans-NIH organizational approach. Dr. Kington commented that both the Institute of Medicine and outside constituent groups have noted the need for this type of coordination. The OPASI will offer transparent, systematic processes to improve the management of the NIH research portfolio; link NIH funding with public health needs and coordinate information on NIH expenditures across 250 disease categories; improve evaluation of the effectiveness of NIH programs; and enable NIH to respond nimbly and dynamically to emerging scientific opportunities and public health concerns. The OPASI will provide new methods, electronic tools, and information to help the ICs improve their management of their science portfolios and to coordinate activities NIH-wide. Dr. Kington anticipated that management of the NIH portfolio will be fully electronic by 2007–08.
The OPASI resides in the Office of the Director, NIH, and consists of three divisions: Division of Resource Development and Analysis, Division of Strategic Coordination, and Division of Evaluation and Systematic Assessments. Among their designated functions, the first division will be responsible for knowledge management, the second will provide an “incubator space” to “jump start” new trans-NIH initiatives in the NIH Roadmap, and the third will coordinate cross-cutting reviews and evaluations and distribute funds to the ICs for evaluation activities.
Dr. Kington noted that the selection and funding of new NIH Roadmap initiatives, which will become the responsibility of OPASI, is proceeding in four stages. The NIH is obtaining input separately from scientists and public representatives, staff, and the public—through scientific consultations, submission of ideas, and input to the OPASI website (http://opasi.nih.gov/). This input will be reviewed and discussed by the NIH Director, IC directors, and Advisory Council to the Director, NIH, who will select and decide on the funding of specific initiatives. A Council of Councils is being established to advise the IC directors during this process. This Council of approximately 30 members will consists of representatives from each IC advisory council and the NIH Council of Public Representatives (COPR).
Initiatives will be funded through the Common Fund, which is being established as a formal structure to pool resources and support shared needs across the NIH and new Roadmap activities. In FY 2007, the Common Fund will comprise approximately 1.6 percent of the total NIH budget. Dr. Kington noted that NIH anticipates expanding the fund up to 5 percent of the total NIH budget, contingent upon NIH budget increases and identification of trans-NIH scientific opportunities and public health needs. The administrative functions of OPASI will be funded within the NIH appropriation. Dr. Kington noted that OPASI is adding budget and staff (e.g., to support expanded Roadmap activities, acquire expertise in knowledge management).
Discussion
In response to Council’s questions, Dr. Kington said that, as in the NIH Roadmap, the funding for new initiatives will be for 5 years and could be extended up to 10 years. In addition, OPASI is developing a “fast-track” process for funding newly emerging opportunities within 1 year. OPASI also is collaborating with the NIH Office of Extramural Research and the Center of Scientific Review on ways to shorten the review process, particularly for newly independent investigators. Commenting on evaluation, Dr. Kington noted that NIH is defining a process for evaluating every trans-NIH initiative and for evaluating OPASI.
The Council emphasized the importance of encouraging and advancing innovative, transformative, and “risk-taking” initiatives and the need for NIH to “be nimble” in responding to emerging opportunities and needs. Dr. Kington agreed and remarked that changing the culture of science is not easy even though science per se is the seeking of change. He noted that the challenge is difficult and that NIH constituents need to continually “push” for this change. Commenting on the difficulty of organizationally generating creativity, Dr. Kington pointed to the success NIH has had in applying dedicated resources to jump start research areas. He suggested that one might view OPASI as the “office of the carrot.”
Dr. Tabak noted that the Common Fund will offer a wealth of opportunity for NIDCR scientists to interact with the broader research environment. He urged the Council members to “get the word out” to their professional colleagues and encourage NIDCR scientists to take full advantage of this opportunity and prepare to apply for the “second wave” of Roadmap funds that will become available in 2007–08. Dr. Pihlstrom noted, in particular, that the Institutional Clinical and Translational Science Award (CTSA) (U54) (RFA-RM-07-002) is a major trans-NIH opportunity for dental researchers to which NIDCR contributes support each year. He noted that “the train is leaving the station” and NIDCR scientists need to become involved in this program.
VII. BIOLOGY OF AAV TRANSDUCTION: APPLICATIONS IN GENE THERAPY
Dr. John A. Chiorini, Tenured Investigator, Adeno-Associated Virus Biology Unit, Gene Therapy and Therapeutics Branch, NIDCR Division of Intramural Research, discussed the benefits, potential applications, and future research directions in using adeno-associated viruses (AAVs) as a vector system for gene transfer. Two goals, which are core elements of the NIDCR intramural research program, are to develop improved vectors for gene transfer and to understand the biology of the vector system.
Dr. Chiorini noted that most of the problems associated with gene therapy relate to the vector systems. The three methods currently used for gene transfer are chemical (e.g., lipids), physical (e.g., microinjections), and biological (i.e., viral). NIDCR researchers are making major advances in development of biological methods and, in particular, use of AAVs to introduce genes into salivary gland cells. Dr. Chiorini said that NIDCR researchers are showing that AAVs are an excellent and versatile vector system. AAVs are naturally defective in replication and genetically simple and easy to manipulate. They induce a minimal host immune response while allowing for long-term gene expression and are biologically a diverse virus family with different serotypes that have distinct cell tropisms and transduction activities. In describing these different properties, NIDCR researchers have determined, for example, that in mouse models AAV5 is more effective in salivary glands than are other serotypes such as AAV2 or AAV4. This research has attracted investigators into the field to identify other not-yet-defined AAV vectors.
Two potential applications of the research are to reengineer cells to gain a function, for the treatment of localized salivary disease (e.g., radiation-induced xerostomia), and to add genes to secrete proteins and treat systemic disease (e.g., Sjögren’s syndrome, hemophilia). Dr. Chiorini noted that the latter application takes advantage of the notable ability of salivary glands to secrete proteins. He said that NIDCR researchers have successfully used an AAV vector encoding interleukin-10 to secrete this immunomodulatory protein locally using the salivary glands’ natural constitutive protein expression pathway and maintain salivary flow in a mouse model of Sjögren’s syndrome. This result suggests the possibility of being able to reverse the course of the disease. Researchers also may be able to take advantage of the same secretory pathway to introduce genes, via AAV, that would stimulate systemic production of protein factor IX in patients with hemophilia B.
Current vectors target ductal cells very efficiently, but not acinar cells which make up a significant portion of the salivary gland and are a critical cell type for salivary gland function. To move beyond the current vectors and to understand the gene expression profiles that are necessary for optimal gene transfer with existing vectors, NIDCR investigators are using comparative gene analysis (CGA), studying cDNA microarrays from panels of cells to identify the genes that are important in this activity. Dr. Chiorini noted one example in which, using CGA, NIDCR researchers identified the platelet-derived growth factor receptor (PDGFR) as the receptor for AAV5 cell entry. Exploring this lead, the researchers have shown that, by increasing the expression of PDGFR, they can increase AAV5-mediated gene transfer to cells and further increase recombinant protein expression.
Dr. Chiorini highlighted four directions for future research in this area: (i) continue to identify vectors and understand their biology, (ii) advance ongoing preclinical studies of them into clinical applications, (iii) continue to define the underlying biology associated with Sjögren’s syndrome and to explore new therapies for the disease (e.g., study other clinically approved immunomodulatory molecules), and (iv) develop vectors able to deliver genes to salivary gland acinar cells. In closing, he noted that the NIDCR intramural program is an exciting place to conduct research, because of the many talented scientists in the program, and a collaborative environment that fosters productive interactions among intramural scientists as well as with the extramural community.
VIII. COUNCIL OPERATING PROCEDURES – REVISION
Dr. Braveman reviewed two sets of proposed changes to the operating procedures of the NADCRC. The draft revised procedures were provided to the Council and posted on the NIDCR website.
Modifications to section II, Secondary Review of Grant Applications, would authorize NIDCR staff to (i) “review and approve or disapprove non-competitive supplements to existing grants” and to report “non-competitive supplements exceeding $100,000 in direct costs” to the Council “for information only.”
A major change, in section IV, Options Available to NIDCR Staff, states that, “in keeping with the Institute’s stated policy of adjusting funding plans during the fiscal year,” staff may give additional consideration when making funding decisions to “filling scientific gaps in the Institute’s research portfolio; potential scientific overlap with grants already supported; whether or not the applicant is a new investigator; and the level of other support available to the applicant.” This revision specifies NIDCR options in “determining the priority funding order of R03, R21, and R01 applications.” It limits these options to “up to 10 percent of the funds available for new or competing renewal applications for a given funding cycle….” Staff may also determine the funding order of Small Business Innovation Research (SBIR) and Small Technology Transfer Research (STTR) applications; career award applications; and applications responding to Requests for Applications.
Dr. Braveman noted that staff decisions regarding the priority funding order of applications would be made subsequent to Council’s secondary review of applications, “vetted through the NIDCR Executive Staff Committee,” documented internally, and presented “at the next meeting of the NADCRC for informational purposes.” “For investigator-initiated applications utilizing other funding mechanisms,” staff would make recommendations for priority funding and “present background information and justification for the recommendation at the [current] Council meeting.” Two Council members would review the recommendation and “provide their assessment, leading to a discussion and vote by the Council.”
Discussion
The Council vigorously discussed the revisions. Members expressed concern about the extramural community’s perception of these changes, and they noted that new electronic capabilities make it possible for the Council to be more proactive and participatory upfront in the secondary review process. Staff emphasized that application of the proposed options would occur only after Council’s secondary review of applications and would be limited, potentially affecting about six grant applications a year. The added flexibility would enable NIDCR to better accommodate budget restrictions and changes; ensure funding support for emerging opportunities, innovative research, and new investigators; and offer Council more information on research priorities than ever before. The Council noted that this issue is a legitimate one for a research organization, that the percentage of grant applications affected would be small, that NIDCR decisions would be made between applications receiving closely similar priority scores from initial review groups, and that staff would report all decisions to Council.
The Council approved a motion to accept the proposed revisions to the NADCRC operating procedures.
Dr. Braveman noted that the revised operating procedures will stand for 1 year and that NIDCR will consider the Council’s comments for the future.
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).
Before closing the session, Dr. Braveman presented the guidelines pertaining to confidentiality of information and materials presented and conflict of interest. He noted that members are required to absent 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.
A report of the Blue Ribbon Panel on the Intramural Program of the NIDCR was presented and discussed.
X. REVIEW OF APPLICATIONS
Grant Review
The Council considered 567 applications requesting $112,770,951 in total costs. The Council recommended 346 applications for a total cost of $67,427,672 (see Attachment II).
ADJOURNMENT
The meeting was adjourned at 3:00 p.m. on September 18, 2006.
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 2006
NOTE: A complete set of open-portion handouts is available
from the Executive Secretary.