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Muscle-Kidney Crosstalk in Age-related Kidney Disease

年龄相关性肾脏疾病中的肌肉-肾脏串扰

基本信息

批准号：
10399649
负责人：
Pei-Hui Lin
金额：
$ 47.05万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399649
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Age Aging Antibiotics Attenuated Biochemical Biology Biomedical Research Blood Circulation Cell membrane Cellular Structures Chronic Chronic Kidney Failure Communication Disease Doxycycline Elderly Engineering Epithelial Epithelial Cells Exercise Exposure to Fibrosis Functional disorder Genes Geriatrics Health Human Individual Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Interleukin-1 beta Intravenous Intravenous infusion procedures Ischemic Preconditioning Kidney Kidney Diseases Knock-out Limb structure Link Mediating Molecular Multicellular Process Mus Muscle Myeloid Cells Names Natural regeneration Operative Surgical Procedures Organ Pathology Physical Exercise Physiological Physiology Play Predisposition Process Proteins Recombinants Renal function Research Role Signal Transduction Skeletal Muscle Stress TNF gene Testing Therapeutic Tissues Translating Transplantation Tubular formation Ureteral obstruction age related aged base canine model cytokine injury and repair kidney fibrosis kidney preservation live cell imaging macrophage mouse model novel preservation prophylactic repaired response tissue repair tool welfare

项目摘要

Project Summary Acute kidney injury (AKI) and chronic kidney disease (CKD) are more prevalent in elderly individuals due to the increased susceptibility to injury and diminished repair capability of the aging kidney. Age-related decline of renal function may reflect multicellular dysfunction that leads to reduced capability of the kidney to repair or regenerate in response to stress. Our group previously identified MG53 as a key component of cell membrane repair, which plays a vital role in protection against AKI. We know that renal proximal tubular epithelia (PTE) contain endogenous MG53 protein. In principle, compromised function of MG53 to repair injury to PTE may be an intrinsic mechanism that contributes to reduced kidney function in aging. We also know that MG53's myokine function in tissue repair is compromised in aging. A loss of the crosstalk from muscle to kidney may constitute an extrinsic mechanism leading to the increased vulnerability of the kidney to function properly during aging. This project is centered on testing the hypothesis that MG53 participates in the multicellular process of aging-related AKI and CKD by maintaining the integrity of PTE cells and facilitating muscle-kidney crosstalk. We have made a novel finding that links MG53's myokine function in control of intracellular Ca signaling to modulation of inflammasome activation associated with kidney injury and fibrosis. Thus, we developed a novel concept that engineering of macrophages with tailored secretion of MG53 can enhance renoprotection via harnessing inflammation and fibrotic remodeling associated with CKD. If proven, these findings can have a significant impact on geriatric medicine research, as chronic inflammation and fibrosis occur during the aging process and can impact the function of many organs including kidney.

项目摘要急性肾损伤（阿基）和慢性肾病（CKD）在老年人中更普遍，这是由于增加对损伤的敏感性和降低老化肾脏的修复能力。肾功能减退功能可能反映多细胞功能障碍，导致肾脏修复或再生能力降低来应对压力。我们的研究小组先前确定MG 53是细胞膜修复的关键成分，在预防阿基方面起着至关重要的作用。我们知道肾近端小管上皮细胞（PTE）含有内源性MG 53蛋白。原则上，MG 53修复PTE损伤的受损功能可能是一种内在的损伤。这是导致衰老时肾功能下降的机制。我们还知道MG 53的肌因子功能，组织修复在老化中受损。从肌肉到肾脏的串扰的损失可能构成外在的这是导致肾脏在衰老过程中功能正常的脆弱性增加的机制。这个项目是中心在于检验MG 53参与衰老相关阿基的多细胞过程的假设， CKD通过维持PTE细胞的完整性和促进肌肉-肾脏串扰。我们写了一本小说这一发现将MG 53的肌因子功能与细胞内Ca信号传导的控制与炎症小体的调节联系起来，活化与肾损伤和纤维化相关。因此，我们开发了一个新的概念，具有定制的MG 53分泌的巨噬细胞可以通过利用炎症增强肾保护，与CKD相关的纤维化重塑。如果得到证实，这些发现可能会对老年人产生重大影响。医学研究，因为慢性炎症和纤维化发生在衰老过程中，包括肾脏在内的许多器官的功能。