Inflammation, muscle wasting, and physical function in chronic kidney disease

描述(由申请人提供)：这项建议的总体目标是促进候选人的发展，成为一名独立的、以患者为导向的研究人员，专注于与慢性肾脏疾病(CKD)及其功能和代谢后遗症相关的骨骼肌病理。这项建议的主要目的是研究炎症如何在透析开始前后影响骨骼肌生理和身体功能的变化。申请者将接受CKD研究专家的重点指导， 肌肉生理学和新陈代谢，并将结合流行病学和分子方法来解决这个问题。这项研究将首次前瞻性地跟踪晚期肾脏疾病患者在其护理的关键过渡时刻：开始透析。我们会 对炎症标志物以及重要的临床和功能参数进行纵向测量。我们将把这些数据与骨骼肌生理学相结合，并将同时评估人类骨骼肌中的多种体内平衡途径。我们的目标是：(1)明确炎症与晚期透析前CKD患者骨骼肌生理、瘦体重和身体功能变化的关系；(2)明确向慢性透析过渡对炎症、骨骼肌稳态、瘦体重和身体功能的影响。没有一项针对慢性肾脏病患者的研究同时在生化、生理和临床水平上检测肌肉萎缩。这项申请包括一个严格的5年职业发展计划，其中包括强化指导的综合战略，研究人体生理学的新研究方法的正式培训，重点教学课程，以及参加研究研讨会和国家科学会议。该计划的很大一部分致力于掌握新的研究方法，使主要研究人员能够在肾脏疾病、肌肉新陈代谢和身体功能的交叉点建立独立的研究计划。总之，这项建议将产生重要的、临床相关的数据，并旨在为研究抗炎治疗对慢性肾脏病患者肌肉萎缩的影响的R01应用程序产生初步数据。集中、集中和跨学科的指导将促进候选人作为研究人员的发展，拥有与临床结果相一致的肌肉萎缩机制研究的专业知识。这项研究提案有可能通过引领未来在预防和治疗肌肉萎缩和功能衰退方面的创新来改善对CKD患者的护理。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to foster the development of the candidate as an independent patient-oriented researcher focusing on skeletal muscle pathology associated with chronic kidney disease (CKD) and its functional and metabolic sequelae. The overarching aim of this proposal is to examine how inflammation affects changes in skeletal muscle physiology and physical function in the period surrounding dialysis initiation. The applicant will receive focused mentoring from experts in the study of CKD, muscle physiology, and metabolism and will combine epidemiological and molecular methods to address this question. This study will be the first to prospectively follow patients with advanced kidney disease in a pivotal moment of transition in their care: the initiation of dialysis. We will perform longitudinal measurements of markers of inflammation and important clinical and functional parameters. We will integrate these data with skeletal muscle physiology, and will simultaneously evaluate multiple homeostatic pathways in skeletal muscle in humans. Our aims are: (1) To define the association of inflammation with changes in skeletal muscle physiology, lean body mass, and physical function in patients with advanced predialysis CKD; and (2) To define the effect of the transition to chronic dialysis on inflammation, skeletal muscle homeostasis, lean body mass, and physical function. No studies in patients with CKD have simultaneously examined muscle wasting at a biochemical, physiologic, and clinical level as we propose. This application includes a rigorous 5 year career development plan that includes an integrated strategy of intensive mentorship, formal training in new research methods for studying human physiology, focused didactic coursework, and participation in research seminars and national scientific meetings. A significant portion of this plan is devoted to mastering new research methods that will enable the primary investigator to establish an independent research program at the intersection of kidney disease, muscle metabolism, and physical function. In summary, this proposal will produce important, clinically relevant data and is intended to generate preliminary data for an R01 application studying the effects of anti-inflammatory therapy on muscle wasting in patients with CKD. Intensive, focused, and interdisciplinary mentoring will foster the candidate's development as an investigator with expertise studying mechanisms of muscle atrophy in concert with clinical outcomes. This research proposal has the potential to improve the care of patients with CKD by leading to future innovations in the prevention and treatment of muscle wasting and functional decline.