The Role of Ankyrin-B Mutations in Premature Senescence

描述(由申请人提供)：研究方案描述了一个为期两年的指导性研究计划，旨在为首席调查员(PI)提供一个在老年研究中追求职业生涯的基础。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获得了心血管疾病和临床心脏电生理学方面的奖学金。他目前是心脏病科医学部的医学讲师。拟议的项目将提高对细胞和分子生物学的熟练程度，并提供描述动物模型的能力。范·贝内特博士将担任国际和平协会科学发展的主要导师。贝内特博士是杜克大学詹姆斯·B·杜克大学细胞生物学教授，霍华德·休斯医学研究所研究员。他有丰富的历史，培养了医学领域的思想领袖。此外，PI的进展将接受由老年研究方面受人尊敬的调查人员组成的咨询委员会的定期科学和职业咨询。贝内特实验室的工作此前已经证实，Ankyrin-B单倍体不足会导致过早衰老和虚弱的多器官综合症。此外，研究还表明，基于Ankyrin-B靶向的干扰会导致多个器官系统的钙动力学改变，从生理上导致老年人常见的疾病，包括窦房结功能障碍、心律失常和葡萄糖耐量减低。这项拟议的研究项目将通过评估两只在非洲血统(L1622I)和欧洲血统(R1788W)个体中发现突变的“敲门”小鼠，寻求进一步评估Ankyrin-B在衰老中的作用。具体目标包括：1)确定L1622I和R1788W突变是否存在生理性表型锚蛋白-B单倍体不足(ankB+/-)；以及2)确定上述突变是否复制了ankB+/-小鼠细胞内钙动力学的破坏。由于在1000多万美国人中存在Ankyrin-B突变，拟议中的研究与公共健康直接相关。杜克大学医学中心为PI提供了一个理想的环境，以启动专注于影响老年人的心血管疾病的多学科研究生涯，因为它提供了接触不同但互补的科学学科的专家的机会。虽然心脏病学部一直处于基础、转译和临床研究的前沿，但老年病学部已经确立了自己作为国家卓越的老年医学项目之一的地位。通过设计一项利用不同研究学科的优势的研究和指导计划，拟议的研究计划最大限度地发挥了首席研究人员的努力，以确立自己在心脏病学、心脏电生理学和老年病学领域的思想领袖地位。

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.