Cellular and Molecular Mechanisms of COVID-19 Mediated Kidney Injury

COVID-19 介导的肾损伤的细胞和分子机制

基本信息

批准号：
10204532
负责人：
Jonathan Himmelfarb
金额：
$ 30.04万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-25 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204532
关键词：
2019-nCoV ANGPT1 gene ATAC-seq Acute Renal Failure with Renal Papillary Necrosis Address Adult Respiratory Distress Syndrome Affect Autopsy Binding Biopsy Blood Vessels Blood Volume CCL2 gene CCL3 gene COVID-19 COVID-19 pandemic CSF3 gene CXCR3 gene Cardiovascular system Case Study Cell Death Cells Cellular Membrane Chromatin Clinical Communities Complex Complication Coronavirus Coronavirus spike protein Critical Care Data Data Set Development Diabetes Mellitus Diabetic Nephropathy Dialysis procedure Disease Economics Endothelial Cells Endothelium Enhancers Epithelial Cells Epitopes Evaluation Fostering Gene Expression Gene Expression Profiling Genes HIV Infections Human IL2 gene IL6 gene IL7 gene Infection Inflammatory Inflammatory Response Injury Injury to Kidney Institutes Intensive Care Units Interleukin-1 Interleukin-10 Kidney Kidney Diseases Kidney Failure Mediating Membrane Membrane Glycoproteins Molecular Morbidity - disease rate Natriuresis Nephrotic Syndrome Organ Patients Peptide Hydrolases Peptidyl-Dipeptidase A Pharmaceutical Preparations Phenotype Physiology Plasma Pneumonia Process Protein Engineering Proteins Proteolysis Public Health Recombinants Regulation Renin-Angiotensin System Research SARS coronavirus Sepsis Septic Shock Serine Protease Serum Signal Pathway Signal Transduction Site Supportive care Surface System TMPRSS2 gene TNF gene Testing Therapeutic Tubular formation Viral Virus Work blood pressure regulation cell type cytokine release syndrome effective therapy epigenomics inhibitor/antagonist kidney cell kidney cortex kidney vascular structure man microphysiology system mortality nephrotoxicity neutralizing antibody novel podocyte prevent receptor receptor binding receptor expression response response to injury success therapeutic candidate therapeutic evaluation therapy design transcriptome sequencing transcriptomics uptake

项目摘要

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.

项目摘要 /摘要正在进行的冠状病毒2019（Covid-19）大流行是由严重的急性呼吸综合症引起的冠状病毒2（SARS -COV -2），导致了超过一百万的病例，大量发病率和死亡率以及广泛的经济和社会破坏。该疾病的发展已显示引起并发症肾衰竭。很明显，肾脏参与互联的多种机制 19个感染正在运作。 30％至40％的严重感染的Covid-19患者患有急性儿童需要在重症监护病房中透析治疗的高比例受伤。而且，来自活检和尸检研究表明肾脏足细胞，近端管状上皮细胞和内皮细胞细胞可能会被SARS -COV -2感染。新兴数据证明了Covid-19 podocyte损伤导致肾病综合征，近端肾小管受累会导致急性肾脏损伤和内皮参与会导致血栓性微血管病 - 因此，肾脏参与可以具有蛋白质临床表现，类似于HIV感染对肾脏的影响。没有特定的治疗方法是目前已针对COVID-19相关肾脏疾病进行了验证，并了解细胞特异性分子肾脏疾病和糖尿病患者中与COVID-19相关的过程可能具有显着对公共卫生的影响。对机制的更好理解将促进有效疗法的发展除了强化重症监护病房的支持性护理外，这已经至关重要这些患者需要与透析相关的治疗。我们的小组开创了“人类肾脏的发展” 片上的微生物生理系统（MPS），概括了肾脏生理学的关键方面机制和对伤害的反应以及测试修复机制。我们将把现有的议员部署到了解COVID-19介导的肾损伤的细胞和分子机制，并测试治疗防止SARS -COV -2引起的肾脏损伤和肾衰竭的策略。