The Role of Ankyrin-B Mutations in Premature Senescence

锚蛋白 B 突变在过早衰老中的作用

• 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
• 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

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）：研究建议描述了一项为期两年的指导研究计划，旨在为首席研究员（PI）提供一个基础，从而从事老年医学研究职业。 PI已在约翰·霍普金斯医院（Johns Hopkins Hospital）和杜克大学医学中心（Duke University Medical Center）的心血管疾病和临床心脏电生理学的奖学金中完成了内科住院医师。他目前是心脏病学系医学系的医学讲师。拟议的项目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。 Vann Bennett博士将成为PI科学发展的主要导师。 Bennett博士是杜克大学詹姆斯·B·杜克（James B.他拥有医学科学的悠久历史培训思想领袖。此外，PI的进度将从老年研究的尊敬的研究人员咨询委员会咨询委员会中获得定期的科学和职业顾问。 Bennett实验室的工作先前已经确定，Ankyrin-B单倍不足会导致早期衰老和脆弱的多器官综合征。此外，这表明，基于Ankyrin-B的靶向靶向的破坏会导致多器官系统中Ca2+动力学的改变，从生理上导致老年人常见的疾病，包括窦淋巴结功能障碍，心律不齐和葡萄糖不耐受。拟议的研究项目将旨在通过评估两只在非洲人（L1622i）和欧洲（R1788W）下降中发现的“敲门蛋白”小鼠来进一步评估Ankyrin-B在衰老中的作用。具体目的包括：1）确定L1622I和R1788W突变在生理上是弯道a骨蛋白 - b单倍弥倍不足（ANKB +/-）； 2）确定上述突变是否存在ANKB +/-小鼠中细胞内Ca2+动力学的破坏。由于Ankyrin-B中的突变存在超过1000万美国人，因此拟议的研究与公共卫生直接相关。 杜克大学医学中心（Duke University Medical Center）为PI提供了一个理想的环境，以发起多学科研究职业，该研究专注于心血管疾病，影响老年人，因为它为各种而互补的科学学科提供了访问权限。尽管心脏病学的分裂一直处于基础，转化和临床研究的最前沿，但老年医学分工已经成为该国杰出的老年医学计划之一。通过设计一个利用不同研究学科优势的研究和指导计划，提议的研究计划最大程度地提出了主要研究者在心脏病学，心脏电生理学和老年病的界面上确立自己的思想领袖的努力。