The Role of Ankyrin-B Mutations in Premature Senescence

锚蛋白 B 突变在过早衰老中的作用

基本信息

批准号：
8317550
负责人：
KENT Ronald NILSSON
金额：
$ 7.85万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8317550
关键词：
Academic Medical Centers Adaptor Signaling Protein Advisory Committees Affect African African American Aging American Amino Acids Animal Model Ankyrins Arrhythmia Atrial Fibrillation Attenuated Basic Science Binding Biochemical Biological Assay Cardiac Cardiac Myocytes Cardiology Cardiovascular Diseases Cardiovascular system Caucasians Caucasoid Race Cell physiology Cellular Assay Cellular biology Clinical Clinical Research Confocal Microscopy Country Cytoskeleton Deterioration Development Discipline Disease Elderly Electrophysiology (science)Employee Strikes Environment Ethnic Origin European Exhibits Family Fellowship Foundations Functional disorder Genetic Geriatrics Glucose Glucose Intolerance Goals Heart Hospitals Human Image In Vitro Individual Inositol Institutes Internal Medicine Investigation Islets of Langerhans Laboratories Life Life Expectancy Longevity Macromolecular Complexes Medical Medicine Membrane Mentors Molecular and Cellular Biology Mus Musculoskeletal Mutation Na(+)-K(+)-Exchanging ATPase Oral Organ Osteoporosis Phenocopy Phenotype Physiological Physiology Population Principal Investigator Proteins Public Health Recording of previous events Research Research Personnel Research Project Grants Research Proposals Residencies Risk Role Science Series Sinus Socioeconomic Status Specific qualifier value Spectrin Syndrome Testing Time Tissues Training Translational Research Universities Vocational Guidance Work base body system career design frailty functional decline genetic association impaired glucose tolerance innovation instructor loss of function mutation novel premature prevent professor programs racial difference receptor research study sarcopenia senescence therapy design

项目摘要

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.

描述（由申请人提供）：研究提案描述了一项为期 2 年的指导研究计划，旨在为首席研究员 (PI) 提供从事老年研究职业的基础。 PI 已在约翰·霍普金斯医院完成了内科住院医师培训，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研究金。他目前是医学系心脏病科的医学讲师。拟议的项目将提高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。 Vann Bennett 博士将担任 PI 科学发展的主要导师。 Bennett 博士是杜克大学细胞生物学 James B. Duke 教授和霍华德休斯医学研究所研究员。他在医学科学领域培养思想领袖方面拥有丰富的历史。此外，PI 的进展将定期接受由老年医学研究领域受人尊敬的研究者组成的咨询委员会提供的科学和职业建议。 Bennett 实验室的工作此前已证实，锚蛋白 B 单倍体不足会导致过早衰老和虚弱的多器官综合征。此外，研究还表明，基于锚蛋白 B 的靶向破坏会导致多个器官系统中 Ca2+ 动力学的改变，从而在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受不良。拟议的研究项目将通过评估两只在非洲 (L1622I) 和欧洲 (R1788W) 血统个体中发现突变的“敲击”小鼠，寻求进一步评估锚蛋白-B 在衰老中的作用。具体目标包括：1)确定L1622I和R1788W突变是否存在生理表型ankyrin-B单倍体不足(ankB+/-)； 2) 确定上述突变是否反映了 ankB+/- 小鼠中细胞内 Ca2+ 动态的破坏。由于锚蛋白-B 突变存在于超过 1000 万美国人中，因此拟议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，以开展多学科研究生涯，重点关注影响老年人的心血管疾病，因为它为 PI 提供了接触不同但互补的科学学科的专家的机会。虽然心脏病学部门一直处于基础、转化和临床研究的前沿，但老年病学部门已成为美国最杰出的老年病学项目之一。通过设计一个利用不同研究学科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员的努力，使自己成为心脏病学、心脏电生理学和老年医学领域的思想领袖。