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)：这项建议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人员。职业发展计划将侧重于教学培训，完成研究项目，以及来自具有不同专业知识的委员会的指导。教学培训将与研究计划直接相关，包括高级纵向建模、生物标记物的使用以及与认知和认知障碍相关的临床和翻译研究方法的课程工作。该研究提案的目标将是评估慢性肾脏疾病(CKD)中认知障碍和脑血管疾病的风险因素。认知障碍和脑血管疾病在CKD中非常普遍，不能用高血压、血脂异常和高血糖等传统危险因素完全解释。成纤维细胞生长因子23(FGF-23)水平随肾功能下降而升高，而可溶性Klotho水平随肾功能下降而下降。高klotho和高klotho均与心血管事件和死亡率的增加相关，而高klotho可导致脑微血管疾病，而低klotho可导致直接的神经损伤。这项拟议的研究将利用两项队列研究(健康老龄化和身体成分研究(Health ABC)和认知与透析研究)和一项临床试验(收缩压干预试验)的数据，研究成纤维细胞生长因子-23和klotho与认知功能和脑血管疾病的横断面和纵向关联。这两项研究涵盖了CKD的所有阶段以及CKD的高危人群。总的假设是CKD的特点是FGF23水平升高和Klotho水平降低，FGF23水平升高和Klotho水平降低与脑血管疾病的发生和认知功能受损有关。其具体目的如下：目的1)在Health ABC中确定成纤维细胞生长因子-23(FGF23)和Klotho与认知功能和脑血管疾病的横断面和纵向关联，目的2)在Sprint的CKD亚组中确定FGF23和Klotho与认知功能、卒中和MRI异常的横断面和纵向关联，目的3)测定一组维持性血液透析患者中的可溶性Klotho，并确定其与认知功能的横断面和纵向关联。所有的目标都是可行的，并且有足够的统计力量。这位候选人已经组建了一个指导委员会，拥有肾病、认知、矿物质代谢以及流行病学和统计学方面的临床研究专业知识。马克·萨纳克博士将担任主要导师。他在成功指导研究员和初级教员方面有着长期的记录，并在心血管疾病、认知及其相关风险因素领域工作了多年。约阿希姆九世博士将担任共同导师。他在CKD的矿物质代谢的翻译和临床研究方面拥有广泛的专业知识，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.