Dissecting the role of soluble a-Klotho in cardiovascular aging

项目摘要/摘要 拟议的职业发展奖将促进和促进候选人的培训和发展 独立调查员。候选人：肯尼斯·林博士是麻省理工学院医学院助理教授 印第安纳大学的肾病学博士。拟议的研究结合了以患者为中心的研究，心肺 运动测试(CPET)技术、蛋白质组学和计算生物学嵌入了严格的培训 计划。导师：莎伦·莫博士(首席导师)曾任美国肾脏病学会主席 (ASN)，临床和翻译研究副院长兼肾脏病学部主任 印第安纳大学。Ravi Thadhani博士(二级导师)是麻省理工学院的首席学术官 和哈佛医学院的系主任。研究：心血管疾病的年龄相关性变化 系统及其并发症是慢性肾脏病(CKD)患者的主要死亡原因。 尽管如此，目前还没有直接治疗这种疾病的方法。Klotho是一种蛋白质 存在于血液循环中，具有高度多效性的抗衰老作用。动物研究表明 Klotho显示了有望用于治疗心血管疾病的治疗特性 慢性肾脏病中的疾病。然而，在未来的人类面前，必须首先解决几个基本问题 干预性研究可以继续进行：第一，已发表的研究循环Klotho与心血管疾病的研究 到目前为止，结果主要集中在形态变化上，而明确的证据表明 衰老与心血管功能储备减少密切相关。其次，准确的水平是 Klotho的各种循环亚型及其在心血管健康中的特殊作用的性质仍然是 未定义。因此，拟议研究的总体目标是弥合我们对 循环Klotho在CKD心血管衰老反应调节中的作用。我们假设 循环中的Klotho缺乏症是CKD心血管过早老化的主要决定因素。 在具体目标1中，我们将描述各种Klotho亚型与心血管疾病的关系 采用最先进的CPET技术进行结构和功能储备。我们将定义循环的级别 Klotho亚型在健康和晚期CKD中(横断面)，以及肾移植后(前瞻性)。 循环中的Klotho亚型水平将使用已建立的免疫沉淀和Western进行评估 吸墨法。 在具体目标2中，我们将进行横断面研究，以表征循环Klotho的关系 使用健康和CKD患者的人体动脉进行早期血管变化的研究。以进一步确定 对于Klotho的治疗特性，我们将使用动脉外植体器官培养进行介入性研究。

PROJECT SUMMARY/ABSTRACT The proposed career development award will foster and promote the candidate’s training and evolution toward independent investigator. Candidate: Dr. Kenneth Lim is Assistant Professor of Medicine in the Division of Nephrology at Indiana University. The proposed study integrates patient-oriented research, cardiopulmonary exercise testing (CPET) technology, proteomics and computational biology embedded in a rigorous training plan. Mentorship: Dr. Sharon Moe (Primary Mentor) is Past President of the American Society of Nephrology (ASN), Associate Dean of Clinical and Translational Research and Director of the Division of Nephrology at Indiana University. Dr. Ravi Thadhani (Secondary Mentor) is Chief Academic Officer at MassGeneralBrigham and Faculty Dean at Harvard Medical School. Research: Age-associated changes of the cardiovascular system and its complications are the leading cause of death in patients with chronic kidney disease (CKD). Despite this, there are currently no direct therapies available to treat this condition today. Klotho is a protein present in circulation that exerts highly pleiotropic aging suppressive effects. Animal studies have demonstrated promising therapeutic properties of Klotho that could be used for the treatment of cardiovascular disease in CKD. However, several fundamental problems must first be overcome before future human interventional studies can proceed: Firstly, published studies examining circulating Klotho with cardiovascular outcomes to-date have focused mainly on morphological alterations, while clear evidence has shown that aging is tightly associated with reduced cardiovascular functional reserve. Secondly, the precise levels of the various circulating isoforms of Klotho and the nature of their specific roles in cardiovascular health are still undefined. The overall aim of the proposed study is therefore to bridge a critical gap in our understanding of the role of circulating Klotho in the regulation of the cardiovascular aging response in CKD. We hypothesize that circulating Klotho deficiency is a major determinant of premature cardiovascular aging in CKD. In specific aim 1, we will characterize the relationship of the various Klotho isoforms with cardiovascular structure and functional reserve using state-of-the-art CPET technology. We will define levels of circulating Klotho isoforms in health and advanced CKD (cross-sectional), and after kidney transplantation (prospectively). Circulating Klotho isoform levels will be assessed using an established immunoprecipitation and western blotting method. In specific aim 2, we will conduct a cross-section study to characterize the relationship of circulating Klotho with premature vascular changes using human arteries from healthy and CKD patients. To further determine therapeutic properties of Klotho, we will conduct an interventional study using arterial explant organ cultures.