Ischemic Kidney Injury and Kidney Repair: Stress Granules

阿基是一种主要的肾脏疾病，其与高死亡率、发病率和增加的肾功能相关。 普遍性。此外，阿基后不完全或适应不良的肾修复导致慢性肾损伤。 病理学，导致CKD。由退伍军人反映的老龄化人口非常容易受到两者的影响 阿基和CKD。阿基的一个关键病理特征是肾小管损伤，因此， 过去的研究集中于肾小管细胞损伤和死亡。然而，据了解，为了响应 损伤时，细胞可能激活内在机制或应激反应以进行自我保护和存活， 只有当这些机制被严重或长期的损伤所压倒或改变时，细胞才会死亡。 应激颗粒（Stress granule，SG）是一种新发现的存在于真核细胞中的胞质结构 胁迫，主要含有RNA和RNA结合蛋白。我们最近展示了第一个 应激肾小管细胞中SG形成的证据。我们已经建立了第一只老鼠 其中核心SG基因G3 BP 1从肾近端小管细胞特异性消融的模型。在 此外，我们还鉴定了CSDE 1作为G3 BP 1的一种新的结合蛋白。这个应用程序的目标是 目的是确定SG在缺血性阿基和适应不良肾修复中的病理作用，并阐明 G3 BP 1和CSDE 1之间的分子相互作用。我们假设：应激颗粒是 在缺血性阿基中诱导，以保护肾小管细胞，但阿基后持续的应激颗粒可能 导致了适应不良的修复CSDE 1通过与G3 BP 1相互作用发挥重要作用 在缺血性阿基等情况下细胞应激期间SG形成中的作用。我们提出了三个具体目标： (1)测试缺血性阿基中诱导应激颗粒以保护肾小管免受损伤的假设。 （2）检验应激颗粒导致适应不良的肾脏修复的假设， 缺血性阿基;（3）检验CSDE 1在应激颗粒中起重要作用的假设 通过与G3 BP 1的相互作用形成。这一应用将揭示应力颗粒在 阿基和AKI后肾修复，并阐明应激颗粒形成中的G3 BP 1/CSDE 1相互作用。 因此，完成这项工作不仅会对压力的调节产生重要的影响， 颗粒，但也可以确定应激颗粒作为阿基和相关疾病的新治疗靶点。 CKD，开辟了一个新的研究领域。

AKI is a major kidney disease that is associated with high mortality, morbidity, and increasing prevalence. Moreover, incomplete or maladaptive kidney repair following AKI leads to chronic renal pathologies, contributing to CKD. Aging population, mirrored by veterans, is highly susceptible to both AKI and CKD. A key pathological feature of AKI is the damage of renal tubules and, accordingly, the past research has focused on tubular cell injury and death. However, it is known that, in response to injury, cells may activate intrinsic mechanisms or stress responses for self-protection and survival, and the cells die only when these mechanisms are overwhelmed or altered by severe or prolonged insult. Stress granule (SG) is a newly discovered, cytoplasmic structure formed in eukaryotic cells upon cell stress, which mainly contains RNAs and RNA-binding proteins. We recently demonstrated the first evidence of SG formation in stressed kidney tubular cells. We have now established the first mouse model in which the core SG gene G3BP1 is specifically ablated from kidney proximal tubule cells. In addition, we have identified CSDE1 as a novel binding protein of G3BP1. The goal of this application is to determine the pathologic role of SG in ischemic AKI and maladaptive kidney repair, and elucidate the molecular interaction between G3BP1 and CSDE1. We hypothesize that: Stress granules are induced in ischemic AKI to protect kidney tubular cells, but persistent stress granules after AKI may contribute to maladaptive repair. Through the interaction with G3BP1, CSDE1 plays an important role in SG formation during cell stress in conditions like ischemic AKI. We propose three specific aims to: (1) test the hypothesis that stress granules are induced in ischemic AKI to protect against renal tubular damage; (2) test the hypothesis that stress granules contribute to maladaptive kidney repair after ischemic AKI; and (3) test the hypothesis that CSDE1 plays an important role in stress granule formation through the interaction with G3BP1. This application will unveil the role of stress granules in AKI and post-AKI kidney repair, and elucidate G3BP1/CSDE1 interaction in stress granule formation. As such, completion of the work will not only gain significant insights into the regulation of stress granules, but may also identify stress granule as a novel therapeutic target for AKI and associated CKD, opening a new field of study.