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.

项目总结/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博士是医学系的助理教授。 印第安纳州大学肾脏科。拟议的研究整合了以患者为导向的研究，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：Sharon莫伊博士（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脏科主任， 印第安纳州大学。Ravi Thadhani博士（中学导师）是MassGeneralBrigham的首席学术官 哈佛医学院院长研究：糖尿病相关的心血管变化 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，目前还没有直接的治疗方法来治疗这种疾病。Klotho是一种蛋白质 存在于循环中，发挥高度多效性的衰老抑制作用。动物研究 证明了Klotho有前途的治疗特性，可用于治疗心血管疾病。 CKD中的疾病然而，在未来的人类发展之前，必须首先克服几个基本问题。 可以进行干预性研究：首先，已发表的研究检查循环Klotho与心血管疾病 迄今为止的结果主要集中在形态学改变上，而明确的证据表明， 衰老与心血管功能储备的降低密切相关。第二，准确的水平， Klotho的各种循环亚型及其在心血管健康中的特定作用的性质仍然是 未定义。因此，拟议研究的总体目标是弥合我们对以下问题的理解中的一个关键差距： 循环Klotho在CKD心血管衰老反应调节中的作用。我们假设 循环Klotho缺乏是CKD患者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。 结构和功能储备使用最先进的CPET技术。我们将定义循环水平 健康和晚期CKD（横断面）以及肾移植后（前瞻性）的Klotho亚型。 循环Klotho亚型水平将使用已建立的免疫沉淀法和Western印迹法进行评估。 印迹法 在具体目标2中，我们将进行一项横断面研究，以描述循环Klotho 使用来自健康和CKD患者的人动脉进行过早的血管变化。以进一步确定 Klotho的治疗特性，我们将使用动脉外植体器官培养物进行干预性研究。

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

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

FGF23 与晚期慢性肾脏病中的心血管结构和功能。

• DOI: 10.34067/kid.0002192022
• 发表时间: 2022
• 期刊: Kidney360
• 作者: Halim,Arvin;Burney,HeatherN;Li,Xiaochun;Li,Yang;Tomkins,Claudia;Siedlecki,AndrewM;Lu,Tzong-Shi;Kalim,Sahir;Thadhani,Ravi;Moe,Sharon;Ting,StephenMS;Zehnder,Daniel;Hiemstra,ThomasF;Lim,Kenneth
• 通讯作者: Lim,Kenneth