Mechanisms of Kidney Injury in COVID-19

COVID-19 肾损伤的机制

基本信息

批准号：
10700050
负责人：
Shreeram Akilesh
金额：
$ 40.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10700050
关键词：
2019-nCoV APOL1 gene Acute Renal Failure with Renal Papillary Necrosis Address Affect Alleles Anatomy Animal Model Autopsy Bacterial Artificial Chromosomes Biological Models Black race COVID-19 COVID-19 pandemic COVID-19 patient Cells Cessation of life Clinical Data Collaborations Data Development Diagnosis Diagnostic Disease Electron Microscopy Foundations Functional disorder Future Genomics Genotype Goals Guide prevention HIV Infections Hispanic Human Immunohistochemistry Immunology In Situ Hybridization In Vitro Individual Infection Inflammatory Injury Injury to Kidney Interferon Type II Kidney Kidney Diseases Laboratories Lung infections Mediating Modeling Molecular Morphology Mus Organoids Pathogenesis Pathologist Pathology Patients Phenotype Physiological Population Heterogeneity Pre-Clinical Model Prevention Prognosis Proteomics Reagent Renal function Research Research Personnel SARS-CoV-2 infection Slice Source Specimen System Therapeutic Intervention Tissues Transgenic Mice Viral Virus Virus Diseases biobank cell type cytokine cytotoxicity defined contribution experimental study high risk human tissue in vitro Model in vivo induced pluripotent stem cell kidney biopsy kidney cell kidney infection mortality risk mouse genetics mouse model prevent response risk variant transcriptomic profiling transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT The SARS-CoV-2 pandemic has infected millions of individuals in the US and caused hundreds of thousands of deaths. We and others have shown that COVID-19 is also strongly associated with devastating and usually rare kidney pathophysiologies, such as collapsing glomerulopathy (CG). As in HIV infection, CG in COVID-19 patients mostly affects individuals with high-risk APOL1 genotypes, which are more prevalent in Black and some Hispanic patients. To guide treatment, there is a pressing need to understand whether COVID-19 nephropathy is due to direct viral infection or indirect mechanisms, such as cytokines or physiologic disturbances that emanate from the lung infection. Addressing this need has been hampered by poorly validated reagents, and misinterpretation of immunohistochemistry and electron microscopy findings. We have assembled a multi-investigator team to uncover the mechanisms of kidney injury due to SARS-CoV-2 infection. We will bring expert and complementary expertise in anatomic, autopsy and renal pathology, integrative genomic analysis, human kidney organoid systems and mouse immunology. We will use primary human tissue specimens, in vitro human kidney model systems and a new mouse model of COVID-19 to define direct and indirect mechanisms of SARS- CoV-2 associated kidney injury in three specific aims. Aim 1: Using kidney tissue specimens from COVID- 19 patients and controls, we will define the spectrum of kidney manifestations in individuals that have been infected with SARS-CoV-2. We will use immunohistochemistry, in situ hybridization, and proteomics to define SARS-CoV-2 kidney infection in a diverse population. In patients with COVID-19 associated CG, we will define molecular changes of this disease using spatial transcriptomic profiling, and the association with APOL1 status. These studies will define the relationship of SARS-CoV-2 infection to COVID-19 associated kidney diseases and uncover molecular mechanisms that underlie direct and indirect modes of kidney injury. Aim 2: Human kidney organoids provide a physiologically relevant model of SARS-CoV-2 infection. We will define cellular, morphologic and molecular hallmarks of SARS-CoV-2 infection in human kidney organoids and organotypic tissue slices. Using established iPSC cells with APOL1 high-risk alleles, we will determine the impact of APOL1 genotype on infection and inflammatory cytokine induced kidney injury. These studies will establish which kidney cells are capable of being infected by SARS-CoV-2, and kidney cell type specific molecular changes induced by viral infection and inflammatory cytokines. Aim 3: We will use a recently developed mouse adapted SARS-CoV-2 virus to determine the effect of SARS CoV-2 infection on kidney function in vivo. Using newly described BAC- transgenic mice that express human APOL1 G0, G1 or G2 alleles, we will define the influence of human APOL1 high-risk alleles on kidney function and kidney injury during SARS-CoV-2 infection. The successful development of these models will establish a paradigm for investigating viral infection associated kidney injury and leverage mouse genetics to define mechanisms of kidney injury and CG, and well as future therapeutic interventions.

项目概要/摘要 SARS-CoV-2 大流行已感染美国数百万人，并导致数十万人死亡死亡人数。我们和其他人已经证明，COVID-19 还与破坏性且通常罕见的疾病密切相关。肾脏病理生理学，例如塌陷性肾小球病（CG）。与 HIV 感染一样，COVID-19 患者中的 CG 主要影响具有高风险 APOL1 基因型的个体，该基因型在黑人和一些西班牙裔美国人中更为普遍患者。为了指导治疗，迫切需要了解 COVID-19 肾病是否是由于直接病毒感染或间接机制，例如细胞因子或源自病毒的生理紊乱肺部感染。验证不佳的试剂和误解阻碍了解决这一需求免疫组织化学和电子显微镜检查结果。我们组建了一个由多位研究者组成的团队揭示 SARS-CoV-2 感染引起的肾损伤机制。我们将带来专家和互补解剖学、尸检和肾脏病理学、综合基因组分析、人类肾脏类器官方面的专业知识系统和小鼠免疫学。我们将使用原代人体组织标本，体外人肾模型系统和新的 COVID-19 小鼠模型，用于定义 SARS 的直接和间接机制 CoV-2 与肾损伤相关的三个具体目标。目标 1：使用来自新冠肺炎的肾组织标本 19 名患者和对照者，我们将定义接受过治疗的个体的肾脏表现范围感染了 SARS-CoV-2。我们将使用免疫组织化学、原位杂交和蛋白质组学来定义不同人群中的 SARS-CoV-2 肾脏感染。对于患有 COVID-19 相关 CG 的患者，我们将定义使用空间转录组分析分析该疾病的分子变化，以及与 APOL1 状态的关联。这些研究将明确 SARS-CoV-2 感染与 COVID-19 相关肾脏疾病的关系以及揭示直接和间接肾损伤模式背后的分子机制。目标 2：人体肾脏类器官提供了 SARS-CoV-2 感染的生理相关模型。我们将定义细胞、形态学人类肾脏类器官和器官组织切片中 SARS-CoV-2 感染的分子特征。使用已建立的具有 APOL1 高风险等位基因的 iPSC 细胞，我们将确定 APOL1 基因型对感染和炎症细胞因子引起的肾损伤。这些研究将确定哪些肾细胞是能够被 SARS-CoV-2 感染，以及病毒诱导的肾细胞类型特异性分子变化感染和炎症细胞因子。目标 3：我们将使用最近开发的适应小鼠的 SARS-CoV-2 病毒以确定 SARS CoV-2 感染对体内肾功能的影响。使用新描述的 BAC- 表达人 APOL1 G0、G1 或 G2 等位基因的转基因小鼠，我们将定义人 APOL1 的影响 SARS-CoV-2 感染期间肾功能和肾损伤的高风险等位基因。开发成功这些模型将建立一个研究病毒感染相关肾损伤和影响的范例小鼠遗传学来定义肾损伤和 CG 的机制，以及未来的治疗干预措施。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multi-omic analysis of human kidney tissue identified medulla-specific gene expression patterns.

对人类肾脏组织的多组学分析确定了髓质特异性基因表达模式。

DOI：
10.1016/j.kint.2023.10.024
发表时间：
2023-11-01
期刊：
Kidney international
影响因子：
19.6
作者：
Stefan Haug;Selvaraj Muthusamy;Yong Li;Galen Stewart;Xianwu Li;Martin Treppner;A. Köttgen;S. Akilesh
通讯作者：
S. Akilesh

Digital spatial profiling of collapsing glomerulopathy.

塌陷性肾小球病的数字空间分析。

DOI：
发表时间：
2022-05
期刊：
影响因子：
19.6
作者：
Smith, Kelly D;Prince, David K;Henriksen, Kammi J;Nicosia, Roberto F;Alpers, Charles E;Akilesh, Shreeram
通讯作者：
Akilesh, Shreeram

Collapsing glomerulopathy: unraveling varied pathogeneses.

塌陷性肾小球病：阐明各种发病机制。