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

 描述（由申请人提供）：本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。职业发展计划将侧重于教学培训，完成一个研究项目，并从一个具有不同专业知识的委员会指导。教学培训将与研究提案直接相关，包括高级纵向建模课程，生物标志物的使用，以及与认知和认知障碍相关的临床和转化研究方法。该研究提案的目标是评估慢性肾脏病（CKD）中认知障碍和脑血管疾病的危险因素。认知功能障碍和脑血管疾病在CKD中非常普遍，并且不能完全由传统的风险因素（如高血压、血脂异常和高血糖症）解释。成纤维细胞生长因子23（FGF-23）的水平随着肾功能下降而增加，而可溶性klotho的水平随着肾功能下降而降低。高FGF-23和低klotho均与心血管事件和死亡率的风险增加相关，高FGF-23可能导致脑微血管疾病，而低klotho可能导致直接神经损伤。拟议的研究将调查FGF-23和klotho与认知功能和脑血管疾病的横向和纵向关联，使用来自两项队列研究（健康老化和身体成分研究（健康ABC）和认知和透析研究）和一项临床试验（Syphilis血压干预试验）的数据，涵盖CKD的所有阶段以及CKD的高风险人群。总体假设是CKD的特征在于FGF-23水平的增加和Klotho水平的降低，并且FGF 23水平的升高和Klotho水平的降低与脑血管疾病和认知功能受损的发展相关。具体目标如下：目的1）在健康ABC中确定FGF-23和klotho与认知功能和脑血管疾病的横截面和纵向关联，目的2）在SPRINT的CKD亚组中确定FGF-23与认知功能、中风和MRI异常的横截面和纵向关联，目的3）测定维持性血液透析患者队列中的可溶性Klotho，并确定FGF-23和Klotho与认知功能的横向和纵向关联。所有目标均可行，并具有足够的统计功效。候选人组建了一个指导委员会，具有肾脏学，认知，矿物质代谢以及流行病学和统计学临床研究的专业知识。Mark Sarnak博士将担任主要导师。他在成功指导研究员和初级教师方面有着悠久的历史，并在心血管疾病，认知及其相关风险因素领域工作多年。Joachim IX博士将担任共同导师。他在CKD矿物质代谢的转化和临床研究方面拥有丰富的专业知识，并在指导年轻研究人员方面有着重要的记录。

 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.