Covid 19 cytokine storm

Covid 19细胞因子风暴

基本信息

批准号：
10279177
负责人：
Sumant Singh Chugh
金额：
$ 56.26万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
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：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279177
关键词：
ACE2 Acute Affect Albuminuria Allergic Antibodies BALB/cJ Mouse Biopsy COVID-19 COVID-19 cytokine storm COVID-19 pandemic COVID-19 pathogenesis COVID-19 patient COVID-19 treatment Cell Nucleus Cell membrane Common Cold Complex Cytokine Receptors Data Development Disease Endothelial Cells Endothelium Feedback Foot Process Genetic Human IL-13Ralpha1 Immune response In Vitro Inbred BALB C Mice Individual Inflammatory Infusion Pumps Injections Injury Integrins Interferon Type II Interleukin 4 Receptor Interleukin-10 Interleukin-13 Interleukin-2 Interleukin-4 Interleukin-6 Kidney Kidney Diseases Knockout Mice Lesion Membranous Glomerulonephritis Modeling Multiple Trauma Mus Organ PTK2 gene Patients Phosphorylation Pilot Projects Population Proteinuria Publishing Receptor Cell Relapse Renal glomerular disease Role SARS-CoV-2 infection STAT6 gene Severity of illness Signal Transduction Site TNF gene TNFRSF1A gene Therapeutic Viral Zinc Fingers adaptive immune response autocrine base coronavirus disease cytokine cytokine release syndrome experience glomerular endothelium in vivo interleukin-13 receptor mesangial cell migration mouse model multiorgan damage novel novel therapeutics paracrine particle podocyte receptor slit diaphragm synergism transcription factor treatment strategy

项目摘要

Abstract The COVID 19 pandemic has been associated with the development of proteinuria in up to 40% of hospitalized patients. This cardinal manifestation of kidney disease is most likely related to effects of the extensive cytokine storm in these patients on glomeruli, the filtering units of the kidney. Using five years of experience with studying cytokine storms related to Common Cold induced relapse of some forms of human kidney disease, we developed four novel “cytokine cocktail” models of the COVID 19 cytokine storm. These cytokine cocktails contain components of the Innate and Adaptive immune response in a specific additive sequence and induce acute albuminuria in mice. Also included in the cocktails is soluble Angiotensin Converting Enzyme 2 (sACE2), a circulating form of the receptor for COVID 19 in humans. The presence of heightened kidney disease in mice that are hypomorphs for the podocyte expressed transcriptional factor Zhx2 may provide a partial genetic basis for greater severity of disease in select populations. Using cytokine depletion and cytokine receptor blockage, we noted that it is possible to developed treatment strategies to treat COVID related kidney disease. In Specific Aim 1, we will conduct mechanistic studies in the podocyte related to the effect of cytokine cocktail on the Interleukin 4 receptor, Interleukin 13 receptor, Tumor Necrosis Factor α receptor, and transmembrane ACE2. In vivo studies using knockout mice and in vitro studies using cultured podocytes will be conducted. In Specific Aim 2, we will investigate mechanisms involved in the pathogenesis of COVID 19 related glomerular disease, especially collapsing glomerulopathy. Mice deficient in glomerular endothelial Integrin β5 expression, podocyte Zhx2 expression, or both will be used. Combination of Integrin β5 expression deficient mice with those also deficient in podocyte cytokine receptors and Tumor Necrosis Factor α receptor will be used to study paracrine and autocrine feedback loops. In Specific Aim 3, we will conduct systematic current cytokine depletion and receptor blockage strategies, and also use them in combination to develop a novel therapeutic paradigm for the treatment of COVID 19 related glomerular disease. It is likely that these depletion strategies will benefit other end organ damage caused by the COVID 19 cytokine storm.

抽象的 COVID 19 大流行与高达 40% 的蛋白尿的发生有关住院患者的这种主要表现很可能与这些患者中广泛的细胞因子风暴对肾小球（肾小球的过滤单位）的影响拥有五年研究与普通感冒相关的细胞因子风暴的经验。诱导某些形式的人类肾脏疾病的复发，我们开发了四本小说“细胞因子” COVID 19 细胞因子风暴的“鸡尾酒”模型这些细胞因子鸡尾酒含有多种成分。特定附加序列中的先天性和适应性免疫反应，并诱导急性小鼠白蛋白尿。鸡尾酒中还含有可溶性血管紧张素转换酶 2。 (sACE2)，人类中 COVID 19 受体的循环形式。足细胞表达转录因子亚型的小鼠的肾脏疾病 Zhx2 可能为特定人群中更严重的疾病提供部分遗传基础。我们注意到，利用细胞因子耗竭和细胞因子受体阻断，有可能开发出治疗新冠肺炎相关肾脏疾病的治疗策略。在具体目标 1 中，我们将在足细胞中进行与以下作用相关的机制研究：白细胞介素 4 受体、白细胞介素 13 受体、肿瘤坏死因子 α 的细胞因子鸡尾酒受体和跨膜 ACE2 使用敲除小鼠进行的体内研究和体外研究。将使用培养的足细胞进行。在具体目标 2 中，我们将研究涉及 COVID 19 发病机制的机制相关的肾小球疾病，特别是肾小球缺陷的小鼠的塌陷性肾小球病。将使用内皮整合素 β5 表达、足细胞 Zhx2 表达或两者的组合。整合素β5表达缺陷小鼠与足细胞细胞因子受体缺陷小鼠的比较肿瘤坏死因子α受体将用于研究旁分泌和自分泌反馈循环。在具体目标 3 中，我们将进行系统性电流细胞因子消耗和受体阻断策略，并将它们结合起来开发一种新的治疗范式这些耗竭策略很可能会治疗 COVID 19 相关的肾小球疾病。有益于由 COVID 19 细胞因子风暴引起的其他终末器官损伤。