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 独立研究者。候选人：肯尼斯·林博士（Kenneth Lim）是一名临床翻译研究员 马萨诸塞州总医院（MGH）和哈佛医学院（HMS）肾脏病。拟议的研究 整合面向患者的研究，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中。指导：Ravi Thadhani博士是 MGH的肾脏病，HMS医学教授和合作伙伴临床试验执行总监 卫生保健。他将与一支由专家组成的多学科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及其并发症的变化是 慢性肾脏疾病（CKD）患者的主要死亡原因。尽管如此，目前没有直接 今天可以治疗这种情况的疗法。 klotho是循环中存在的一种蛋白质 多效性衰老抑制作用。动物研究表明 可用于治疗CKD中心血管疾病的Klotho。但是，有几个基本 必须首先克服问题，然后再进行人性介入研究：首先，出版 研究以心血管结局为迄今为止的循环klotho的研究主要集中在 形态学的改变，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 他们在心血管健康中特定角色的性质仍然不确定。此外，临床研究迄今 评估循环klotho受到缺乏可靠的Klotho分析的限制。提议的总体目的 因此，研究是为了弥合我们对循环klotho在调节中的作用的关键差距 CKD中的心血管衰老反应。我们假设循环klotho缺乏是主要的 CKD中心血管衰老过早的决定因素。 在特定目标1中，我们将表征各种klotho同工型与心血管的关系 使用最先进的CPET技术的结构和功能储备。我们将定义循环的水平 Klotho在健康和晚期CKD（横截面）以及肾脏移植后（前瞻性）。 循环klotho同工型水平将使用已建立的免疫沉淀和西方评估 印迹法。此外，拟议的研究将为验证并确认新的平台 我们已经开发出的靶向蛋白质组学测定法，以评估循环klotho同工型的精确评估。 在特定的目标2中，我们将进行横截面研究，以表征循环klotho的关系 使用健康和CKD患者的人动脉进行过早的血管变化。进一步确定 克洛索（Klotho）的治疗特性，我们将使用动脉外植体培养物进行介入研究。