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

基本信息

批准号：
9923642
负责人：
David Alan Drew
金额：
$ 19.44万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923642
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 Structure Training Translational Research Vascular Diseases Vascular calcification Work blood pressure intervention cardiovascular risk factor career development cognitive development cognitive function cognitive performance cognitive testing cohort disorder subtype 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 stroke risk vascular risk factor

项目摘要

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.

描述（由适用提供）：该提案的长期目标是促进候选人的科学发展，以确保成功过渡到独立的临床研究者。职业发展计划将重点介绍教学培训，完成研究项目以及具有潜水员专业知识的委员会的心理。教学培训将与研究计划具有直接相关性，包括有关高级纵向建模，生物标志物以及与认知和认知障碍有关的临床和翻译研究方法的课程。研究建议的目的是评估慢性肾脏疾病（CKD）中认知障碍和脑血管疾病的危险因素。认知障碍和脑血管疾病在CKD中非常普遍，不能完全用传统的危险因素（例如高血压，血脂异常和高血糖）来解释。随着肾功能的下降，成纤维细胞生长因子23（FGF-23）的水平增加，而固体klotho的水平随着肾功能的下降而降低。高FGF-23和低klotho都与心血管事件和死亡率的风险增加相关，而高FGF-23可能会导致大脑中的微血管疾病，而低klotho可能会导致直接的神经系统损害。 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.总体假设是CKD的特征是FGF-23水平的增加，具体目的的下降如下：目标1）确定FGF-23和Klotho与确定功能和脑疾病的横截面和纵向关联，与健康ABC中的脑性疾病相关，以确定与跨跨性别和远程合作的相关性，以确定FGFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFIN的效果均为23-23-23-23-23 Sprint的CKD亚组中的异常，目标3）在一系列维持血液透析患者队列中主张固体klotho，并确定FGF-23和Klotho具有认知功能的横截面和纵向关联。所有目标都是可行的，并且具有足够的统计能力。该候选人已与肾脏病，认知，矿物质代谢以及流行病学和统计的临床研究专家组成心理委员会。马克·萨尔纳克（Mark Sarnak）博士将担任主要导师。多年来，他在心血管疾病，认知及其相关危险因素方面曾在成功进行心理训练的研究员和初级教师方面有着悠久的记录。 Joachim IX博士将担任副主管。他在CKD中的矿物质代谢翻译和临床研究方面拥有广泛的专业知识，并具有指导年轻研究人员的重要记录。