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

项目摘要/摘要 急性肾损伤(AKI)是一种导致肾功能突然下降的疾病。Aki已关联 与发病率、死亡率和医疗保健费用有关。不幸的是，住院患者AKI的发生率 仍在增加。此外，从AKI中恢复不完全会导致慢性肾脏疾病(CKD)，而且在 一些病例，终末期肾病，这也与显著的发病率、死亡率和费用有关。至 迄今为止，我们缺乏方法来预测哪些患者将遭受AKI的长期后遗症和AKI的治疗 除了支持性的照顾。 外体，纳米大小的胞外囊泡已经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信模式。我们最近 明确了外切体在肾小管生长中的作用，这是肾小管所必需的。 AKI患者受损肾脏的再生。鉴于临床治疗的缺乏和AKI之间的关键联系 和CKD，我们将重点关注AKI中释放的外切体是否是一种内源性恢复机制，即 可能是一种既治疗AKI又预防CKD的工具。这项建议调查了尿外切体蛋白的作用。 AKI后的恢复：AIM 1将研究外切体是如何产生的，以及它们对体外愈合的影响 以及培养皿上的小管中的小管生长。我们将操纵调节性基因的表达和/或突变 蛋白质在外切体生物发生中的作用，以确定手法对肾小管生长的影响。 目的2研究外切体控制释放在AKI小鼠体内模型中的作用。使用纵向 AKI期间释放的尿外切体的分析，外切体不能胜任的靶蛋白的病毒传递，以及 工程外切体介导的蛋白质传递，我们将研究外切体负载蛋白在肾脏中的作用 小管再生。急性肾损伤时近端肾小管和近端至远端肾小管内外切体的信号传递 也将被确定。这些研究的结果将确定外切体的释放是否是内源性的 AKI后的恢复机制，并可能产生治疗靶点以及候选预后 AKI患者未来研究的生物标志物。

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.