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: 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
• 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

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）是医学助理教授 印第安纳大学的肾脏病。拟议的研究整合了面向患者的研究，心肺 锻炼测试（CPET）技术，蛋白质组学和计算生物学嵌入了严格的培训 计划。指导：Sharon Moe博士（主要导师）是美国肾脏学会的前任主席 （ASN），临床和转化研究副院长，肾脏科学系主任 印第安纳大学。 Ravi Thadhani博士（次要导师）是Massgenerbrigham的首席学术官 和哈佛医学院的教师院长。研究：与年龄相关的心血管变化 系统及其并发症是慢性肾脏疾病（CKD）患者死亡的主要原因。 尽管如此，目前尚无直接疗法可用于治疗这种情况。克洛托是一种蛋白质 出现在循环中执行高度多效性衰老抑制作用。动物研究有 具有可用于治疗心血管的Klotho的有希望的治疗特性 CKD中的疾病。但是，必须首先克服几个基本问​​题 介入研究可以进行：首先，发表的研究检查了循环的klotho klotho 迄今为止的成果主要集中在形态学的改变上，而明确的证据表明 衰老与减少心血管功能储备密切相关。其次，确切的水平 Klotho的各种循环同工型及其在心血管健康中的特定角色的性质仍然 不明确的。因此，拟议研究的总体目的是弥合我们对 循环克洛索在CKD中心血管衰老反应调节中的作用。我们假设 循环的klotho缺乏症是CKD中过早心血管老化的主要决定因素。 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。 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。

项目成果

Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing.

• DOI: 10.3389/fphys.2020.572355
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Lim K;McGregor G;Coggan AR;Lewis GD;Moe SM
• 通讯作者: Moe SM

Impaired arterial vitamin D signaling occurs in the development of vascular calcification.

• DOI: 10.1371/journal.pone.0241976
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lim K;Molostvov G;Lubczanska M;Fletcher S;Bland R;Hiemstra TF;Zehnder D
• 通讯作者: Zehnder D

The Role of Nonenzymatic Post-translational Protein Modifications in Uremic Vascular Calcification.

• DOI: 10.1053/j.ackd.2019.10.001
• 发表时间: 2019-11
• 期刊: Advances in chronic kidney disease
• 影响因子: 2.9
• 作者: Kenneth Lim;Sahir Kalim

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.

• DOI: 10.1161/jaha.122.025656
• 发表时间: 2022-07-19
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 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-shi;Moe, Sharon M.;Moorthi, Ranjani;Coggan, Andrew R.;McGregor, Gordon;Hiemstra, Thomas F.;Zehnder, Daniel;Lim, Kenneth
• 通讯作者: Lim, Kenneth

Klotho in Kidney Transplantation: A New and Important Target?

肾移植中的 Klotho：一个新的重要目标？

• DOI: 10.1097/tp.0000000000004332
• 发表时间: 2023
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Lim,Kenneth;Chen,Neal;Hato,Takashi
• 通讯作者: Hato,Takashi