The association of FGF-23 and Klotho with cognitive impairment and cerebrovascular disease in chronic kidney disease

FGF-23和Klotho与慢性肾脏病认知障碍和脑血管疾病的关系

• 批准号: 9304203
• 负责人: David Alan Drew
• 金额: $ 19.38万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304203
• 关键词: Adverse effects; Affect; Age Factors; Aging; Area; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Body Composition; Brain; Brain Diseases; Cardiovascular Diseases; Cardiovascular system; Cerebrovascular Disorders; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Cognition; Cognitive; Cohort Studies; Cross-Sectional Studies; Data; Dementia; Development; Diabetes Mellitus; Dialysis procedure; Dyslipidemias; Education; Elderly; Ensure; Epidemiology; Event; Exhibits; Faculty; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fostering; Goals; Health; Heart; Hemodialysis; High Prevalence; Hippocampus (Brain); Human; Hyperglycemia; Hypertension; Impaired cognition; Incidence; Intervention Trial; Kidney; Kidney Diseases; Knockout Mice; Left Ventricular Hypertrophy; Lipids; Magnetic Resonance Imaging; Maintenance; Mediator of activation protein; Memory; Mental Depression; Mentors; Metabolism; Microvascular Dysfunction; Minerals; Modeling; Mus; Nephrology; Nervous System Trauma; Neurons; Outcome; Participant; Pathway interactions; Patients; Population; Premature aging syndrome; Program Development; Renal function; Research; Research Methodology; Research Personnel; Research Project Grants; Research Proposals; Risk Factors; Role; Severities; Statistical Models; Stroke; Subgroup; Training; Translational Research; Vascular Diseases; Vascular calcification; Work; cardiovascular risk factor; career development; cognitive development; cognitive function; cognitive performance; cognitive testing; cohort; executive function; falls; fibroblast growth factor 23; high risk; longitudinal analysis; mild cognitive impairment; modifiable risk; mortality; public health relevance; racial diversity; randomized trial; statistics

 DESCRIPTION (provided by applicant): The long-term objective of this proposal is to foster the scientific development of the candidate to ensure successful transition to an independent clinical investigator. A career development program will focus on didactic training, completion of a research project, and mentoring from a committee with diverse expertise. Didactic training will be of direct relevance to the research proposal including coursework on advanced longitudinal modeling, use of biomarkers, and clinical and translational research methods related to cognition and cognitive impairment. The goal of the research proposal will be to evaluate risk factors for cognitive impairment and cerebrovascular disease in chronic kidney disease (CKD). Cognitive impairment and cerebrovascular disease are highly prevalent in CKD and cannot be fully explained by traditional risk factors such as hypertension, dyslipidemia, and hyperglycemia. Levels of fibroblast growth factor 23 (FGF-23) increase as kidney function declines, while levels of soluble klotho decrease as kidney function declines. High FGF-23 and low klotho have each been associated with an increased risk for cardiovascular events and mortality, and high FGF-23 may cause microvascular disease in the brain while low klotho may result in direct neurological damage. The proposed study will investigate the cross-sectional and longitudinal association of FGF-23 and klotho with cognitive function and cerebrovascular disease using data from two cohort studies (Health Aging and Body Composition Study (Health ABC) and the Cognition and Dialysis Study) and one clinical trial (Systolic Blood Pressure Intervention Trial), spanning all stages of CKD as well those at high risk for CKD. The overall hypothesis is that CKD is characterized by an increase in levels of FGF-23 and a decrease in levels of klotho, and that higher levels of FGF 23 and lower levels of Klotho are associated with the development of cerebrovascular disease and impaired cognitive function. The specific aims are as follows: Aim 1) To determine the cross-sectional and longitudinal association of FGF-23 and klotho with cognitive function and cerebrovascular disease in Health ABC, Aim 2) To determine the cross-sectional and longitudinal association of FGF-23 with cognitive function, stroke, and MRI abnormalities in the CKD subgroup of SPRINT, Aim 3) To assay soluble Klotho in a cohort of maintenance hemodialysis patients and determine the cross- sectional and longitudinal association of FGF-23 and Klotho with cognitive function. All Aims are feasible and have sufficient statistical power. The candidate has assembled a mentoring committee with expertise in clinical research in nephrology, cognition, mineral metabolism, as well as epidemiology and statistics. Dr. Mark Sarnak will serve as the Primary Mentor. He has a long track record of successfully mentoring fellows and junior faculty and has worked in the area of cardiovascular disease, cognition and its associated risk factors for many years. Dr. Joachim Ix will serve as the Co-Mentor. He has extensive expertise in translational and clinical research on mineral metabolism in CKD and has a significant track record of mentoring young investigators.