Cellular and Molecular Mechanisms of COVID-19 Mediated Kidney Injury

项目摘要/摘要 正在进行的2019年冠状病毒(新冠肺炎)大流行是由严重急性呼吸综合征引起的 冠状病毒2型(SARS-CoV-2)，并已导致100多万报告病例，显著发病率和 死亡率，以及广泛的经济和社会混乱。这种疾病的发展已被证明是导致 到并发症肾功能衰竭。越来越清楚的是，COVID中肾脏受累的多种机制- 手术治疗感染19例。30%至40%严重感染新冠肺炎的患者发生急性肾脏 需要在重症监护病房接受透析治疗的比例很高的损伤。此外，证据来自于 活检和尸检研究显示，肾脏足细胞、近端肾小管上皮细胞和内皮细胞 细胞可能感染SARS-CoV-2新兴数据显示新冠肺炎足细胞损伤 导致肾病综合征，近端肾小管受累导致急性肾损伤，内皮细胞 受累导致血栓性微血管病变--因此，新冠肺炎肾脏受累可产生蛋白质 临床表现，类似于HIV感染对肾脏的影响。没有具体的治疗方法 目前已被验证可用于新冠肺炎相关肾脏疾病，并了解细胞特异性分子 肾脏疾病和糖尿病患者与新冠肺炎相关的过程可能会有显著的 对公众健康的影响。对这一机制的更好理解将促进有效疗法的发展 除了重症监护病房的支持性护理，这已经是至关重要的，因为许多 这些患者需要与透析相关的治疗。我们团队开创了人类肾脏研究的先河- 芯片上的微生理系统(MPS)，概括了肾脏生理学的关键方面，评估 损伤的机制和反应，并测试修复机制。我们将把现有的议员部署到 了解新冠肺炎介导的肾损伤的细胞和分子机制，并探讨其治疗方法 预防SARS-CoV-2所致肾损伤和肾功能衰竭的策略。

PROJECT SUMMARY / ABSTRACT The ongoing coronavirus 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), and has led to over one million reported cases, significant morbidity and mortality, and extensive economic and societal disruption. The development of the disease has shown to lead to complications kidney failure. It is becoming clear that multiple mechanisms of kidney involvement in COVID- 19 infection are operative. Between 30 and 40% of severely infected COVID-19 patients develop Acute Kidney Injury with a high proportion requiring dialysis therapy in the Intensive care Unit. Moreover, evidence from biopsy and autopsy studies is emerging that kidney podocytes, proximal tubular epithelial cells and endothelial cells may become infected with SARS‑CoV‑2. Emerging data demonstrate that COVID-19 podocyte injury leads to nephrotic syndrome, proximal tubular involvement leads to acute kidney injury, and endothelial involvement leads to thrombotic microangiopathy – thus COVID-19 kidney involvement can have protean clinical manifestations, analogous to the effects of HIV infection on the kidney. No specific treatment is currently validated for COVID-19 related kidney disease, and understanding the cell-specific molecular processes associated with COVID-19 in patients with kidney disease and diabetes can have a significant impact on public health. A better understanding of the mechanism will foster development of effective therapies beyond the supportive care in the intensive critical care unit, which is already critically important as many of these patients require dialysis-related therapy. Our group has pioneered the development of `human kidney- on-a-chip' microphysiological systems (MPS), which recapitulate critical aspects of kidney physiology, assess the mechanisms and response to injury, and test reparative mechanisms. We will deploy our existing MPS to understand the cellular and molecular mechanisms of COVID-19 mediated kidney injury, and test therapeutic strategies to prevent kidney injury and kidney failure due to SARS‑CoV‑2.