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: 10155477
• 负责人: Kenneth Lim
• 金额: $ 15.57万
• 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/10155477
• 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.

项目总结/文摘