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.

项目概要急性肾损伤（AKI）和慢性肾病（CKD）在老年人中更为常见，因为衰老的肾脏更容易受伤，修复能力下降。与年龄相关的肾功能衰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下降以应对压力。我们课题组之前发现MG53是细胞膜修复的关键成分，在预防 AKI 方面发挥着至关重要的作用。我们知道肾近端肾小管上皮（PTE）含有内源性 MG53 蛋白。原则上，MG53 修复 PTE 损伤的功能受损可能是一种内在的机制。导致衰老过程中肾功能下降的机制。我们还知道 MG53 的肌因子功能组织修复在衰老过程中受到损害。从肌肉到肾脏的串扰损失可能构成外在因素导致肾脏在衰老过程中正常发挥功能的脆弱性增加的机制。这个项目是重点测试 MG53 参与衰老相关 AKI 的多细胞过程的假设通过维持 PTE 细胞的完整性并促进肌肉-肾脏串扰来治疗 CKD。我们写了一本小说发现将 MG53 的肌因子功能控制细胞内 Ca 信号转导与炎症小体的调节联系起来与肾损伤和纤维化相关的激活。因此，我们开发了一个新的概念，即工程具有定制分泌 MG53 的巨噬细胞可以通过利用炎症和与 CKD 相关的纤维化重塑。如果得到证实，这些发现将对老年医学产生重大影响医学研究认为，衰老过程中会发生慢性炎症和纤维化，并会影响包括肾脏在内的许多器官的功能。