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Preserving physical function in patients with kidney disease

保护肾病患者的身体机能

基本信息

批准号：
10460411
负责人：
Matthew K Abramowitz
金额：
$ 70.43万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-03 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460411
关键词：
Age Biopsy Caring Cells Chronic Chronic Kidney Failure Collagen Data Deposition Development Dialysis procedure End stage renal failure Extracellular Matrix Fatty acid glycerol esters Fibrosis Functional disorder Goals Homeostasis Human Impairment Intervention Kidney Diseases Kidney Failure Leg Lower Extremity Magnetic Resonance Imaging Measures Mechanics Mediator of activation protein Methods Molecular Morbidity - disease rate Muscle Muscle satellite cell Muscular Atrophy Nature Outcome Pathology Patient-Focused Outcomes Patients Performance Persons Physical Function Physical Performance Physicians Process Proteomics Race Relaxation Resolution Severities Skeletal Muscle Symptoms Testing Time Tissues Translating Translations United States Walking base blood filtration clinical practice clinically relevant crosslink disability experience frailty functional decline functional improvement healthy volunteer improved improved outcome innovation mortality muscle strength novel strategies predicting response preservation prevent primary outcome proteomic signature quadriceps muscle reduced muscle strength satellite cell secondary outcome sex transcriptome sequencing transcriptomics translational approach

项目摘要

Project Summary/Abstract Skeletal muscle dysfunction contributes to frailty, disability, and mortality in patients with chronic kidney disease (CKD). This proposal seeks to determine if muscle dysfunction in CKD can be alleviated by dialysis (blood filtration for kidney failure). We recently discovered that patients with CKD experience progressively worsening muscle fibrosis, and that greater severity of fibrosis is associated with reduced muscle strength and physical function. In patients with severe CKD, fibrotic changes are extensive. However, despite the seemingly advanced nature of this fibrotic transformation, patients starting dialysis experienced marked improvement in fibrosis. This suggests that, in patients with severe CKD and muscle fibrosis, the initiation of dialysis could improve physical function. Therefore, this proposal tests the highly innovative hypothesis that the initiation of dialysis in patients with severe CKD reverses muscle fibrosis and improves physical function. We will accomplish this objective using a translational approach that integrates clinically relevant functional endpoints with state-of-the-art methods including muscle tissue mechanics, quantitative magnetic resonance imaging (qMR), and transcriptomic and proteomic studies of human skeletal muscle. The proposed human studies will (1) define the effect of dialysis initiation on muscle fibrosis by examining changes in muscle collagen content, collagen cross-linking, tissue passive stiffness, and qMR measures; (2) determine the extent to which regression of fibrosis after dialysis initiation translates into functional improvements by testing the association of alterations in the structural parameters from Aim 1 with changes in muscle strength, endurance, and lower extremity performance; and (3) identify molecular and cellular predictors of the resolution of fibrosis using transcriptomic and proteomic analyses of skeletal muscle. If our hypotheses are correct: (1) muscle fibrosis could be an indicator for physicians to start dialysis therapy; and (2) this proposal will identify an intervention to alleviate muscle dysfunction in patients with CKD.

项目总结/摘要骨骼肌功能障碍导致慢性阻塞性肺疾病患者的虚弱、残疾和死亡肾病（CKD）。该提案旨在确定CKD中的肌肉功能障碍是否可以通过透析缓解（肾衰竭的血液过滤）。我们最近发现， CKD患者的肌肉纤维化进行性恶化，纤维化与降低的肌肉力量和身体功能有关。患者严重CKD，纤维化改变广泛。然而，尽管看似先进的性质，在这种纤维化转化中，开始透析的患者在以下方面有显著改善：纤维化这表明，在严重CKD和肌肉纤维化患者中，透析可改善机体功能。因此，这一建议考验了高度创新的假设重度CKD患者开始透析可逆转肌肉纤维化，改善身体功能。我们将使用一种转化方法来实现这一目标，将临床相关功能终点与最先进的方法（包括肌肉）相结合组织力学、定量磁共振成像（qMR）和转录组学，人类骨骼肌的蛋白质组学研究。拟议的人体研究将（1）定义透析开始对肌肉纤维化的影响通过检查肌肉胶原蛋白含量的变化，胶原交联、组织被动刚度和qMR测量;（2）确定透析开始后纤维化的消退转化为功能改善，测试目标1中结构参数的改变与肌肉力量、耐力和下肢表现;以及（3）鉴定分子和使用转录组学和蛋白质组学分析的纤维化消退的细胞预测因子骨骼肌如果我们的假设是正确的：（1）肌肉纤维化可能是一个指标，医生开始透析治疗;（2）该提案将确定一种干预措施， CKD患者的肌肉功能障碍。