Targeting Microvesicles in Kidney Disease

靶向肾脏疾病中的微泡

• 批准号: 10287960
• 负责人: Chiswili Yves Chabu
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287960
• 关键词: Algae; Animal Model; Ascorbic Acid; Binding; Biogenesis; Biology; Biotin; Cell membrane; Cells; Chronic Kidney Failure; Communication; Development; Diabetic Nephropathy; Distant; Drosophila genus; Drosophila melanogaster; Dyes; Epithelial; Eukaryota; Event; Exposure to; Genetic; Glucose Transporter; Goals; Grant; Homeostasis; Human; Image; Immunoprecipitation; Insulin Resistance; Kidney; Kidney Diseases; Knowledge; Label; Laboratories; Lead; Maps; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Molecular Target; Morphologic artifacts; Multivesicular Body; Organ; Outcome; Pathogenesis; Pathology; Patients; Peroxidases; Physical environment; Physiological; Physiology; Play; Polycystic Kidney Diseases; Precipitation; Prevention; Process; Proteins; Proteomics; RNA Interference; Radial; Role; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; System; Therapeutic; Tissues; Validation; Vesicle; Visualization; Work; base; diabetic patient; exosome; extracellular vesicles; fly; follow-up; human disease; imaging approach; in vivo; intercellular communication; kidney fibrosis; knock-down; lipophilicity; microvesicles; mouse model; mutant; nephrogenesis; novel; novel therapeutics; secretion process; spatiotemporal; tissue culture; vesicle transport; vesicular release

PROJECT SUMMARY Extracellular vesicles (EV) transport and deliver signaling molecules to distant cells to support metabolic processes, kidney development and homeostasis. Deregulation of EV signals are associated with metabolic and chronic kidney disease. EV cargo inhibit glucose transporters, leading to insulin resistance. In addition, EV stimulate profibrotic factors to drive kidney fibrosis in diabetic patients. Furthermore, EV are implicated in the pathogenesis of polycystic kidney disease. Despite the growing realization that EV play a vital role in kidney disease, our basic knowledge of the molecular principles that control EV formation and cargo loading remains fundamentally limited. Identifying and targeting molecules that control EV biogenesis in predictive animal models has the potential to lead to novel and synergizing therapeutics for the benefit of kidney disease patients. EV release is an evolutionary conserved process from algae to flies to humans, suggesting that broadly generalizable molecular requirements for this process exist. Drosophila melanogaster has been invaluable in the discovery of conserved signaling dynamics relevant to human diseases, including nephropathies. To begin to explore the molecular mechanism of EV release and cargo loading, we have developed an in vivo EV labeling system in Drosophila epithelial tissues. This system permits the visualization of EV secretion steps in live imaging approaches. Importantly, we have adapted this system for EV proteomic studies aimed at identifying novel regulators of EV biogenesis and cargo loading. Further, the system is amenable to targeted genetic mutant analyses, permitting robust functional validation of putative EV regulators. In this exploratory R21 grant, we are proposing to use our systems to identify novel EV regulators. Validated regulators will form the basis of a follow- up R01 grant focused on delineating the underlying mechanisms using tissue culture and murine models of chronic kidney disease.

项目摘要 细胞外囊泡（EV）转运并传递信号分子到远处的细胞中，以支持代谢 过程，肾脏发展和体内平衡。 EV信号的放松管制与代谢和 慢性肾脏疾病。 EV货物抑制葡萄糖转运蛋白，导致胰岛素抵抗。另外，EV 刺激纤维化因子在糖尿病患者中驱动肾脏纤维化。此外，EV与 多囊性肾脏疾病的发病机理。尽管越来越意识到EV在肾脏中起着至关重要的作用 疾病，我们对控制电动汽车形成和货物负荷的分子原理的基本知识 从根本上有限。 在预测动物模型中识别和靶向控制EV生物发生的分子具有潜力 导致新颖和协同疗法的肾脏疾病患者。 EV释放是从藻类到苍蝇到人类的进化保守过程，表明广泛地表明 存在该过程的可概括分子要求。果蝇Melanogaster在 发现与人类疾病有关的保守信号动力学，包括肾病。开始 探索EV释放和货物加载的分子机制，我们开发了一个体内EV标记 果蝇上皮组织中的系统。该系统允许在实时成像中可视化EV分泌步骤 方法。重要的是，我们已经将该系统适应了旨在识别新颖的EV蛋白质组学研究 EV生物发生和货物加载的调节剂。此外，该系统适合靶向遗传突变体 分析，允许对推定的EV调节器进行鲁棒的功能验证。在此探索性R21赠款中，我们是 建议使用我们的系统来识别新型的EV调节器。经过验证的监管机构将构成后续的基础 - 提高R01赠款的重点是使用组织培养和鼠模型来描述基本机制 慢性肾脏疾病。