Sharon Gordon - US grants

[unreadable] DESCRIPTION (provided by applicant): Oral mucositis is a dose-limiting consequence of cancer therapy, often leading to pain, treatment alterations, and decreased quality of life. The mechanisms underlying the pathogenesis of oral mucositis remain incompletely elucidated; as a consequence, optimal treatment strategies have not been established. Most research has focused on the toxicity of cancer therapy, using growth factors to boost regeneration of quickly proliferating epithelial cells destroyed as a bystander effect of cytotoxic agents. Our interest in its pathogenesis lies in the inflammatory response mediated by pro-inflammatory cytokines, particularly TNF-alpha, which initiates mucosal signaling, the resultant inflammatory cascade, and the upregulation of proteolysis and apoptosis resulting in tissue injury and pain. Because TNF-alpha is a key early mediator of inflammation, it is an ideal therapeutic target for mucositis. Among the available TNF-alpha inhibitors, we select thalidomide. Our preliminary data suggest that thalidomide is bioavailable at the tissue level when topically applied and is present in the saliva of patients with mucositis. Available evidence suggests that administration of thalidomide topically will suppress the mucosal inflammatory cascade without the high circulating drug levels and adverse effects associated with enteral thalidomide. However, prior to further development of this intervention it is necessary to establish safety, tolerability, dose, and dosing interval in human subjects. We will test our hypotheses in three specific aims utilizing pharmacologic and molecular approaches in healthy volunteers and patients with oral mucositis. The first two Aims will test the hypothesis that topical thalidomide demonstrates tolerability and safety as measured by incidence of adverse events and plasma drug concentrations with increasing dose in healthy volunteers (Aim 1) and in patients with mucositis (Aim 2). Aim 3 will establish proof of principle by correlating the pro-inflammatory cytokine TNF-alpha with the clinical sign of mucositis and the symptom of pain, and will refine data collection techniques in the outpatient setting. Analysis of these data will contribute to dose selection, timing of intervention and observations, and molecular and clinical endpoints to be evaluated in a future Phase ll/lll study of topical thalidomide mouth rinse for mucositis. Demonstration of safety and tolerability will provide a basis to test further this route of administration. Hence, this proposal holds promise for clinical application in a relatively short period. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The overall goal of the Dual Degree Scholars in Clinical Oral Health Research Training (DDS-COHRT) Program is to provide clinical research training in multidisciplinary, team research settings to train dentists as clinical investigators in order to improve oral and craniofacial health through applied research. Our primary aim is to 1) prepare dentists to become independent investigators in clinical research. The secondary aim is to 2) train dentists to contribute to clinical research as part of a multi-disciplinary research team. Training via the Masters in Clinical Research (MSCR) or the Masters in Public Health (MPH) will include: 1) a core didactic curriculum for the methodologic and analytic concepts central to clinical research, 2) research experiences that include participation in an ongoing clinical research project and development of an individual clinical research project, and 3) training in career development-related skills. Trainees will be able to take advantage of: 1) the availability of outstanding mentors in clinical and public health research; 2) a well-established institutional research infrastructure, including: the GCRC and its Genomics, Statistics, and Bioinformatics Cores, the Center for Clinical Trials, the Greenebaum Cancer Center, and the curriculum in Clinical Research and associated MSCR supported by an NIH K30 award; 3) the MPH programs offered by the University of Maryland at Baltimore and at College Park, and 4) geographic proximity to research training partners at the University of Maryland campuses, the NIH, and Johns Hopkins University, making additional mentors and courses available. The DDS-COHRT Program will include 3 components: 1) formal study in clinical research methods with didactic coursework, seminars, and workshops, 2) a team-mentored research practicum and research project, and 3) a unique senior year of dental school to facilitate re-entry into the clinical curriculum and prepare students for an academic career. Program participants will engage in 5 years of training, graduating with the combined DDS-MSCR or DDS-MPH degrees. The primary research training period will occur between the junior and senior years of dental school, although short-term training periods will be provided from the freshman through the senior years of dental school. The extant resources and mentors will permit trainees to undertake projects in all types of clinical research: patient-oriented research, translational research, small- and large-scale clinical studies and trials, and epidemiologic studies. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall goal of the comprehensive training program in Oral and Craniofacial Biology is to train highly skilled, interactive basic and clinical scientists who can successfully address the expanding research opportunities in dental, oral and craniofacial research. At the University of Maryland, we have demonstrated the ability to provide an environment of flexible but integrated training opportunities in dental, oral and craniofacial research. By offering a broad selection of training options which serves a diverse population of college, dental, PhD and combined DDS-PhD students as well as junior and mid-career faculty, we plan to accomplish our primary objective of developing independent investigators in basic, clinical, and translational research. Secondary objectives are to train individuals to become important contributors to larger multidisciplinary research teams and to generate an appreciation of the need for continued oral health research in all of our students. The training program capitalizes on the unique geographic proximity between major medical centers in the City of Baltimore and Washington, D.C. and includes an expert faculty of more than 60 established scientists to provide mentoring for students and dental faculty. Training is organized around four major thematic areas of strength in clinical and basic research. These thematic areas of expertise are Hard Tissue and Neoplastic Diseases, Infectious and Autoimmune Diseases, Oral and Craniofacial Chronic Sensory Disorders, and Oral and Craniofacial Motor Disorders. Primary emphasis is placed on cross-disciplinary approaches that involve integration of basic, translational and clinical research in each trainee program. Toward this end we are initiating new partnerships with the School of Medicine. We plan to offer a new curriculum of formal clinical training for postdoctoral dentists and we are consolidating our graduate education into a system of campus-wide interdepartmental graduate programs in basic and translational science. Our program design includes a horizontal organization in which basic and clinical research trainees interact across disciplines and a vertical organization which provides more experienced trainees the opportunity to train younger scientists. We are particularly dedicated to enhanced training opportunities for underrepresented minorities and women in research relevant to improvement of oral health and better treatment of oral diseases.