Regulation of exosome release and its role in acute kidney injury.

外泌体释放的调节及其在急性肾损伤中的作用。

• 批准号: 10163179
• 负责人: Kenneth Kwon
• 金额: $ 34.65万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163179
• 关键词: Acetylation; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Biogenesis; Biological; Biological Markers; Cells; Chronic Kidney Failure; Clinical; Disease; Distal; End stage renal failure; Endosomes; Epithelial Cells; Fingerprint; Future; G-Protein-Coupled Receptors; Gene Expression; Genes; Growth; Health Care Costs; Immunity; In Vitro; Incidence; Knock-out; Label; Link; Lysine; MAP Kinase Gene; Measures; Mediating; Methods; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Pathway interactions; Patients; Physiological; Production; Prognostic Marker; Protein Engineering; Proteins; Recovery; Regulation; Renal function; Renal tubule structure; Role; Signal Transduction; Supportive care; Testing; Therapeutic; Tissues; Tubular formation; Urine; Viral; Virus; apical membrane; base; cost; engineered exosomes; exosome; extracellular vesicles; genetic regulatory protein; healing; in vivo; intercellular communication; kidney cell; longitudinal analysis; mortality; mouse model; nanoscale; new therapeutic target; organ injury; prevent; renal damage; renal epithelium; response; therapeutic target; tool; urinary; wound healing

Project Summary/Abstract Acute kidney injury (AKI) is a condition that results in an abrupt decrease in renal function. AKI is associated with morbidity, mortality, and health care costs. Unfortunately, the incidence rate of AKI in hospitalized patients is still increasing. Furthermore, incomplete recovery from AKI leads to chronic kidney disease (CKD), and in some cases, end-stage renal disease, which is also associated with significant morbidity, mortality, and cost. To date, we lack methods to predict which patients will suffer long-term sequelae from AKI and treatments for AKI except for supportive care. Exosomes, nanometer-sized extracellular vesicles have been recognized as a fingerprint of the cellular states, as well as a mode of intercellular communication in physiological and pathophysiological conditions. We recently identified the role of exosomes in renal cell tubule growth, which is recapitulated and required for renal tubule regrowth from damaged kidneys in AKI. Given the lack of clinical therapies and the critical links between AKI and CKD, we will focus on whether exosomes released in AKI is an endogenous recovery mechanism, which might be a tool to both treat AKI and prevent CKD. This proposal investigates the role of urinary exosome proteins in recovery following AKI: Aim 1 will investigate how exosomes are produced, and their impact on in vitro healing and tubule growth in the tubules-on-dish. We will manipulate the gene expression and/or mutation of regulatory proteins in exosome biogenesis, in order determine the effects of the manipulation in renal cell tubule growth. Aim 2 will investigate the role of controlled exosome release in in vivo mouse models of AKI. Using longitudinal analyses of urinary exosomes released during AKI, viral delivery of exosome-incompetent target proteins, and engineered exosome-mediated protein delivery, we will investigate the role of exosome-loaded proteins in renal tubule regrowth. Signal transfer via exosomes within proximal tubules and proximal-to-distal tubules during AKI will be determined as well. The results of these studies will determine if exosome release is an endogenous recovery mechanism following AKI, and may generate therapeutic targets, as well as candidate prognostic biomarkers for future studies in patients suffering from AKI.

项目总结/摘要 急性肾损伤（阿基）是一种导致肾功能突然下降的疾病。阿基与 发病率、死亡率和医疗费用。不幸的是，住院患者中阿基的发生率 仍在增加。此外，从阿基的不完全恢复导致慢性肾病（CKD），并且在某些情况下， 某些情况下，终末期肾病，这也与显著的发病率、死亡率和成本相关。到 迄今为止，我们缺乏方法来预测哪些患者将遭受阿基的长期后遗症和阿基的治疗 除了支持性治疗 外泌体，纳米大小的细胞外囊泡已被认为是细胞状态的指纹， 以及生理和病理生理条件下的细胞间通讯模式。我们最近 确定了外泌体在肾小管细胞生长中的作用，这是肾小管生长所需的， 阿基中受损肾脏的再生。鉴于临床治疗的缺乏以及阿基与其他疾病之间的关键联系， 和CKD，我们将重点关注阿基中释放的外泌体是否是一种内源性恢复机制， 可能是治疗阿基和预防CKD的工具。这项提议调查了尿外泌体蛋白的作用 阿基后的恢复：目标1将研究外泌体是如何产生的，以及它们对体外愈合的影响 和小管在培养皿上的生长。我们将操纵基因表达和/或突变的调节 外泌体生物发生中的蛋白质，以确定操作在肾细胞小管生长中的作用。 目的2将研究受控外泌体释放在阿基的体内小鼠模型中的作用。使用纵向 阿基期间释放的尿外泌体的分析，外泌体不胜任的靶蛋白的病毒递送，以及 工程外泌体介导的蛋白质递送，我们将研究外泌体负载的蛋白质在肾脏疾病中的作用。 小管再生阿基期间近端小管和近端-远端小管内通过外泌体的信号传递 也将被决定。这些研究的结果将确定外泌体释放是否是内源性的。 阿基后的恢复机制，并可能产生治疗靶点，以及候选预后 用于未来阿基患者研究的生物标志物。