The Role of Ankyrin-B Mutations in Premature Senescence

DESCRIPTION (provided by applicant): The research proposal describes a 2-year mentored-research plan designed to provide the principal investigator (PI) with a foundation from which to pursue a career in geriatric research. The PI has completed a residency in Internal Medicine at the Johns Hopkins Hospital and fellowships in both Cardiovascular Diseases and Clinical Cardiac Electrophysiology at Duke University Medical Center. He is currently a Medical Instructor in the Department of Medicine, Division of Cardiology. The proposed project will promote proficiency in cellular and molecular biology, as well as provide the ability to characterize animal models. Dr. Vann Bennett will serve as the primary mentor for the PI's scientific development. Dr. Bennett is the James B. Duke Professor of Cell Biology at Duke University and a Howard Hughes Medical Institute Investigator. He has an extensive history training thought leaders in the medical sciences. In addition, the PI's progress will receive regular scientific and career counsel from an advisory committee of respected investigators in geriatric research. Work in the Bennett laboratory has previously established that ankyrin-B haploinsufficiency results in a multi-organ syndrome of premature senescence and frailty. In addition, it has demonstrated that disruption of ankyrin-B based targeting results in alterations in Ca2+ dynamics in multiple organ systems that physiologically result in diseases commonly found in the elderly, including sinus node dysfunction, arrhythmias and glucose intolerance. The proposed research project will seek to further evaluate the role of ankyrin-B in aging by evaluating two "knockin" mice that harbor mutations found in individuals of African (L1622I) and European (R1788W) descent. Specific aims include: 1) determine whether the L1622I and R1788W mutations physiologically phenocopy ankyrin-B haploinsufficiency (ankB+/-);and 2) determine whether the aforementioned mutations phenocopy the disruption in intracellular Ca2+ dynamics seen in ankB+/- mice. As mutations in ankyrin-B are present in over 10 million Americans, the proposed research has direct relevance to public health. Duke University Medical Center provides the PI with an ideal environment to launch a multi- discipline research career focused on cardiovascular conditions affecting the elderly as it offers access to experts in diverse, yet complementary, scientific disciplines. While the division of cardiology has been at the forefront of basic, translational, and clinical research, the division of geriatrics has established itself as one of the preeminent geriatrics programs in the country. By designing a research and mentoring plan that takes advantage of the strengths of the different research disciplines, the proposed research plan maximizes the principal investigator's efforts to establish himself as a thought leader at the interface of cardiology, cardiac electrophysiology and geriatrics. PUBLIC HEALTH RELEVANCE: Disruption of ankyrin-B based targeting of membrane-spanning proteins recently has been associated with a novel syndrome of frailty and premature senescence characterized by arrhythmias, impaired glucose tolerance, musculoskeletal deterioration and a reduced life span. The proposed line of investigation described in "The Role of Ankyrin-B Mutations in Premature Senescence," aims to clarify the role of ankyrin-B in the pathophysiology of aging. As over 10 million Americans are projected to harbor loss-of-function mutations in ankyrin-B, the proposed research has direct relevance to public health.