Longitudinal Assessment of Skeletal Muscle Physiology in Dialysis Patients

 描述（由申请人提供）：职业发展计划：我有证据审查以及慢性肾病（CKD）相关肌肉骨骼并发症流行病学的背景，通过我在终末期肾病（ESRD）患者运动研究中的工作评估身体表现的经验，以及设计和分析CKD患者的试点试验以表征其肌肉骨骼健康的经验。在本K23中，我将在一项队列研究中前瞻性研究肌肉减少（肌肉减少症），以确定新透析患者的临床指标和生物标志物。我将在一项前瞻性队列研究中进行评估，并通过流行病学和生物统计学技术的高级课程、生物标志物测量的基本工具和临床试验设计来加强这种实践培训。我将参加全国性的肌肉骨骼健康和肾脏病会议。我有一个多学科的指导团队，由肌肉骨骼生理学，肌肉质量和体能评估，生物标志物和CKD临床试验的科学家组成。我的主要导师Sharon莫伊博士在成功指导肾脏病学初级教师和CKD肌肉骨骼疾病转化研究的校外支持方面有着令人羡慕的记录。印第安纳州大学（IU）在这一领域拥有丰富的研究资源：1）多个部门和学校的肌肉骨骼疾病领域的研究人员2）专业的研究生课程和期刊俱乐部，以及3）高质量的设备和设施的可用性。我有一个部门的主席承诺，以保护我的研究生涯的75%的时间。研究计划总结：透析患者有显著的肌肉减少症，这与住院率和死亡率增加相关。我的总体假设是，接受透析的患者骨骼肌再生受损，导致进行性活动障碍和/或死亡。我将进行性活动障碍定义为1年内步态速度下降0.1 m/s。为了验证这一点，我将利用100名患者的数据，这些患者入组了一项正在进行的事件透析患者多中心研究（称为“LUCID”）的IU队列。在目标1中，我将评估肌肉质量和力量指标，以确定发生进行性活动障碍的透析患者亚组以及该关系的关键协变量和混杂因素。在目标2中，我将研究骨骼肌再生的循环生物标志物与i）肌肉减少症和ii）进行性活动障碍之间的关系。在目标3中，我将利用整个美国LUCID队列（n=750），并确定肌肉再生的循环标志物水平是否增加了预测透析患者死亡率的能力 已知的危险因素。这些转化研究将增强我对肌肉减少症的病理生理学的理解，并量化其临床变化，以确定将从未来的干预性试验中受益的患者，针对我计划进行的肌肉减少症。我的长期目标是改善肾病患者的肌肉骨骼健康。

 DESCRIPTION (provided by applicant): Career Development Plan: I have a background in evidence review as well as in epidemiology of Chronic Kidney Disease (CKD) associated musculoskeletal complications, experience in the assessment of physical performance through my work on a study of exercise in end-stage renal disease (ESRD) patients, and experience in designing and analyzing pilot trials in CKD patients to characterize their musculoskeletal health. In this K23 I will prospectively study muscle loss (sarcopenia) in a cohort study in order to identify its clinical indicators and biomarkers in patients new to dialysis. I will perform assessments in a prospective cohort study and augment this hands-on-training with advanced coursework in epidemiology and biostatistics techniques, basic tools for biomarker measurements and clinical trial design. I will attend national meetings on Musculoskeletal Health and Nephrology. I have a multidisciplinary mentoring team made of scientists in musculoskeletal physiology, muscle mass and physical performance assessment, biomarkers and in the conduct of clinical trials in CKD. Dr. Sharon Moe, my primary mentor has an enviable track record of successfully mentoring junior faculty in nephrology and extramural support in translational research in musculoskeletal disease in CKD. Indiana University (IU) has a wealth of resources for research in this field: 1) investigators in the field of musculoskeletal disease i multiple departments and schools 2) specialized graduate level courses and journal clubs, and 3) the availability of high quality equipment and facilities. I have a commitment from the Chairman of the Department to protect 75% of my time for research career. Research Plan Summary: Dialysis patients have significant sarcopenia which is associated with increased hospitalizations and mortality. My global hypothesis is that patients undergoing dialysis have impaired skeletal muscle regeneration that leads to progressive mobility impairment and/or mortality. I define progressive mobility impairment as a decrease in gait speed of 0.1 m/s over 1 year. To test this, I will utilize data from 100 patients enrolled in the IU cohort of an ongoing, multi-center study of incident dialysis patients, called "LUCID". In Aim 1, I will evaluate muscle mass and strength measures that identify the subset of dialysis patients that develop progressive mobility impairment and key covariates and confounders of that relationship. In Aim 2, I will study the relationship between circulating biomarkers of skeletal muscle regeneration and i) sarcopenia and ii) progressive mobility impairment. In Aim 3 I will utilize the entire US LUCID cohort (n=750) and determine whether levels of circulating markers of muscle regeneration increase the ability to predict mortality in incident dialysis patients, when combined with known risk factors. These translational research studies will enhance my understanding of the pathophysiology of sarcopenia and quantify its clinical changes to identify patients that will benefit from future interventional trials, targeting sarcopenia that I plan to conduct. My long ter goal is to improve musculoskeletal health in patients with kidney disease.