Dissecting the role of soluble a-Klotho in cardiovascular aging

剖析可溶性α-Klotho在心血管衰老中的作用

• 批准号: 10432907
• 负责人: Kenneth Lim
• 金额: $ 5.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432907
• 关键词: Age; Aging; Animals; Arteries; Biological; Biological Assay; Blood Circulation; Blood Vessels; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Collection; Computational Biology; Conflict (Psychology); Coronary artery; Coupling; Data; Detection; Employment; Enrollment; Evolution; Exercise Test; Exhibits; Fostering; Future; General Hospitals; Health; Healthcare; Human; Immunoprecipitation; In Vitro; Intervention Studies; Investigation; K-Series Research Career Programs; Kidney Failure; Kidney Transplantation; Left Ventricular Hypertrophy; Link; Longevity; Massachusetts; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Morphology; Mus; Nature; Nephrology; Organ Culture Techniques; Outcome; Patients; Performance; Phenotype; Process; Property; Protein Isoforms; Proteins; Proteomics; Public Health; Publishing; Regulation; Research; Research Personnel; Risk; Role; Serum; Specificity; Structure; Study Section; Subgroup; Surrogate Markers; Technology; Testing; Therapeutic; Training; Transgenic Organisms; Vascular calcification; Western Blotting; age related; arterial stiffness; base; cardiovascular health; cohort; human tissue; innovation; klotho protein; medical schools; multidisciplinary; patient oriented research; premature; professor; prospective; response; restoration; skill acquisition; translational scientist; translational study

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 a clinical-translational investigator at the Division of Nephrology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS). The proposed study integrates patient-oriented research, cardiopulmonary exercise testing (CPET) technology, proteomics and computational biology embedded in a rigorous training plan. Mentorship: Dr. Ravi Thadhani is the Chief of Nephrology at the MGH, Professor of Medicine at HMS and Executive Director of Clinical Trials at Partners Healthcare. He will serve as the primary mentor in conjunction with a multidisciplinary team of expert collaborators. 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. Additionally, clinical studies to-date assessing circulating Klotho are limited by the lack of a reliable Klotho assay. 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. Additionally, the proposed study will provide a robust platform to validate and confirm a new targeted proteomics assay that we have developed for the precision assessment of circulating Klotho isoforms. 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.

项目概要/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：Kenneth Lim 博士是该部门的临床转化研究员 马萨诸塞州总医院 (MGH) 和哈佛医学院 (HMS) 肾脏病学中心。拟议的研究 整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 计算生物学嵌入严格的培训计划中。导师：Ravi Thadhani 博士是 MGH 肾脏病学教授、HMS 医学教授和 Partners 临床试验执行总监 卫生保健。他将与多学科专家团队一起担任主要导师 合作者。研究：与年龄相关的心血管系统变化及其并发症是 慢性肾病（CKD）患者死亡的主要原因。尽管如此，目前还没有直接的 目前可用于治疗这种疾病的疗法。 Klotho 是一种存在于循环系统中的蛋白质，具有很强的作用 多效性抑制衰老作用。动物研究显示了有希望的治疗特性 Klotho 可用于治疗 CKD 中的心血管疾病。然而，几个基本 未来的人体介入研究必须首先克服问题才能进行：首先，发表 迄今为止，检查循环 Klotho 与心血管结局的研究主要集中在 形态改变，而明确的证据表明衰老与减少密切相关 心血管功能储备。其次，Klotho 和 Klotho 的各种循环亚型的精确水平 它们在心血管健康中的具体作用的性质仍不清楚。此外，迄今为止的临床研究 由于缺乏可靠的 Klotho 检测，评估循环 Klotho 受到限制。拟议的总体目标 因此，研究的目的是弥合我们对循环 Klotho 在调节中的作用的理解中的一个关键差距。 CKD 中心血管衰老反应的研究。我们假设循环 Klotho 缺乏症是一个主要的 CKD 中心血管早衰的决定因素。 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。我们将定义流通水平 健康和晚期 CKD（横断面）以及肾移植后（前瞻性）中的 Klotho 亚型。 将使用已建立的免疫沉淀和蛋白质印迹法评估循环 Klotho 亚型水平。 印迹法。此外，拟议的研究将提供一个强大的平台来验证和确认新的 我们开发的靶向蛋白质组学检测用于精确评估循环 Klotho 亚型。 在具体目标 2 中，我们将进行横断面研究来表征循环 Klotho 的关系 使用来自健康和 CKD 患者的人类动脉进行过早的血管变化。为进一步确定 鉴于 Klotho 的治疗特性，我们将利用动脉外植体器官培养物进行介入研究。