The Role of Ankyrin-B Mutations in Premature Senescence

描述（由申请人提供）：研究计划描述了一个为期2年的指导研究计划，旨在为首席研究员（PI）提供从事老年研究的基础。他在约翰霍普金斯医院完成了内科实习，并在杜克大学医学中心完成了心血管疾病和临床心脏电生理学的研究。他目前是心脏科医学系的医学讲师。该计划将促进细胞和分子生物学的熟练程度，并提供表征动物模型的能力。范恩·贝内特博士将担任PI科学发展的主要导师。他是杜克大学细胞生物学的詹姆斯·b·杜克教授和霍华德·休斯医学研究所的研究员。他在培养医学领域的思想领袖方面有着丰富的经验。此外，由老年病研究领域受人尊敬的调查人员组成的咨询委员会将定期为PI的进展提供科学和职业咨询。Bennett实验室的工作先前已经证实，锚蛋白b单倍不足会导致多器官过早衰老和虚弱。此外，研究表明，基于锚蛋白b的靶向破坏导致多器官系统Ca2+动力学的改变，从而在生理上导致老年人常见疾病，包括窦房结功能障碍、心律失常和葡萄糖耐受不良。拟议的研究项目将寻求进一步评估锚蛋白b在衰老中的作用，通过评估两个“敲入”小鼠，这些小鼠携带在非洲（L1622I）和欧洲（R1788W）血统的个体中发现的突变。具体目的包括：1)确定L1622I和R1788W突变是否引起锚蛋白- b单倍不足（ankB+/-）的生理表型；2)确定上述突变是否反映了ankB+/-小鼠细胞内Ca2+动力学的破坏。由于超过1000万美国人存在锚蛋白b突变，因此拟议的研究与公共卫生直接相关。杜克大学医学中心为PI提供了一个理想的环境，以开展多学科的研究事业，重点关注影响老年人的心血管疾病，因为它提供了接触不同但互补的科学学科专家的机会。虽然心脏科一直处于基础研究、转化研究和临床研究的前沿，但老年病科已经成为全国最杰出的老年病项目之一。通过设计一个研究和指导计划，利用不同研究学科的优势，建议的研究计划最大限度地发挥首席研究员的努力，使自己成为心脏病学，心脏电生理学和老年病学界面的思想领袖。

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.