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

基本信息

批准号：
10630417
负责人：
Kenneth Lim
金额：
$ 5.18万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630417
关键词：
Age Aging American Animals Arteries Award Biological Biological Assay Blood Circulation Blood Vessels Cardiopulmonary Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chronic Kidney Failure Clinical Research Collection Computational Biology Conflict (Psychology)Coronary artery Coupling Data Employment Enrollment Evolution Exercise Test Exhibits Faculty Fostering Future Health Human Immunoprecipitation In Vitro Indiana Intervention Studies Investigation K-Series Research Career Programs Kidney Failure Kidney Transplantation Left Ventricular Hypertrophy Link Longevity Mass Spectrum Analysis Medical 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 Societies Structure Study Section Subgroup Surrogate Markers Techniques Technology Testing Therapeutic Training Transgenic Organisms Translational Research United States National Institutes of Health Universities Vascular calcification Western Blotting age related arterial stiffness base cardiovascular health cohort human tissue innovation klotho protein medical schools patient oriented research premature professor prospective response restoration skill acquisition translational study

项目摘要

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.

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研究者：Kenneth Lim 博士是医学部的助理教授。印第安纳大学的肾脏病学研究整合了以患者为导向的研究、心肺研究。运动测试（CPET）技术、蛋白质组学和计算生物学嵌入严格的训练中指导计划：Sharon Moe 博士（主要导师）是美国肾脏病学会前任主席。 (ASN)，临床和转化研究副院长兼肾病科主任印第安纳大学 Ravi Thadhani 博士（二级导师）是 MassGeneralBrigham 的首席学术官哈佛医学院院长，研究方向：心血管的年龄相关变化。系统及其并发症是慢性肾脏病（CKD）患者死亡的主要原因。尽管如此，目前还没有直接的疗法可以治疗这种疾病。Klotho 是一种蛋白质。存在于循环系统中，具有高度多效性的衰老抑制作用。 Klotho 有前景的治疗特性可用于治疗心血管疾病然而，在未来的人类面前，必须首先克服一些基本问题。介入研究可以继续进行：首先，已发表的研究检查循环 Klotho 与心血管的关系迄今为止的结果主要集中在形态变化上，而明确的证据表明其次，衰老与心血管功能储备的降低密切相关。 Klotho 的各种循环同工型及其在心血管健康中的具体作用的性质仍不清楚因此，拟议研究的总体目标是弥合我们理解上的一个关键差距。循环 Klotho 在调节 CKD 心血管衰老反应中的作用。循环 Klotho 缺乏是 CKD 心血管早衰的主要决定因素。在具体目标 1 中，我们将描述各种 Klotho 亚型与心血管的关系我们将使用最先进的 CPET 技术来定义结构和功能储备。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。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 患者的人类动脉来进一步确定早期血管变化。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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of kidney donation on bone mineral metabolism.

捐肾对骨矿物质代谢的影响。

DOI：
发表时间：
2020
期刊：
影响因子：
3.7
作者：
Hiemstra, Thomas F;Smith, Jane C;Lim, Kenneth;Xu, Dihua;Kulkarni, Shreya;Bradley, J Andrew;Paapstel, Kaido;Schoenmakers, Inez;Bradley, John R;Tomlinson, Laurie;McEniery, Carmel M;Wilkinson, Ian B
通讯作者：
Wilkinson, Ian B

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.

透析的开始与心血管功能受损有关。

DOI：
发表时间：
2022-07-19
期刊：
影响因子：
5.4
作者：
Arroyo, Eliott;Umukoro, Peter E;Burney, Heather N;Li, Yang;Li, Xiaochun;Lane, Kathleen A;Sher, S Jawad;Lu, Tzong;Moe, Sharon M;Moorthi, Ranjani;Coggan, Andrew R;McGregor, Gordon;Hiemstra, Thomas F;Zehnder, Daniel;Lim, Kenneth
通讯作者：
Lim, Kenneth

Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

晚期 CKD 和肾移植后的差向维生素 D 与心血管结构和功能。

DOI：
发表时间：
2024-01-31
期刊：
影响因子：
0
作者：
Arroyo, Eliott;Leber, Cecilia A;Burney, Heather N;Li, Yang;Li, Xiaochun;Lu, Tzong;Jones, Glenville;Kaufmann, Martin;Ting, Stephen M S;Hiemstra, Thomas F;Zehnder, Daniel;Lim, Kenneth
通讯作者：
Lim, Kenneth

Vitamin D and Atherosclerotic Cardiovascular Disease.