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

• 批准号: 10244886
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10244886
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Age; Aging; Antibiotics; Attenuated; Biochemical; Biology; Biomedical Research; Blood Circulation; Canis familiaris; 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; Modeling; 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; cytokine; injury and repair; kidney fibrosis; kidney preservation; live cell imaging; macrophage; mouse model; novel; preservation; prophylactic; repaired; response; tissue repair; tool; welfare

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(AKI)和慢性肾脏疾病(CKD)在老年人中更常见，原因是 增加对损伤的敏感性，降低老化肾脏的修复能力。年龄相关性肾功能减退 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 以应对压力。我们的小组之前发现MG53是细胞膜修复的关键成分，它 在预防AKI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 衰老时肾功能减退的机制。我们还知道MG53的S肌动因子在 随着年龄的增长，组织修复会受到影响。从肌肉到肾脏的串扰的丧失可能构成外在的 导致肾脏在衰老过程中更容易发挥正常功能的机制。这个项目是 以验证MG53参与衰老相关AKI多细胞过程的假说为中心 CKD通过维持PTE细胞的完整性和促进肌肉-肾脏的串扰来实现。我们已经写了一部小说 发现MG53的S肌动因子调控细胞内钙信号与调节炎症体有关 激活与肾脏损伤和纤维化有关。因此，我们提出了一种新的概念，即工程学 具有MG53定制分泌的巨噬细胞可以通过控制炎症和 与慢性肾脏病相关的纤维化重塑。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，可能会影响 包括肾脏在内的许多器官的功能。