Covid 19 cytokine storm

Covid 19细胞因子风暴

基本信息

批准号：
10675520
负责人：
Sumant Singh Chugh
金额：
$ 62.65万
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/10675520
关键词：
ACE2 Acute Acute Renal Failure with Renal Papillary Necrosis 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 Cytoplasm Data Development Disease Endothelial Cells Endothelium Feedback Foot Process Genetic Homeobox Hospitalization 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 Membrane 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 cell motility 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 transmission process 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大流行与蛋白尿的发展有关40％住院的患者。这种肾脏疾病的主要表现很可能与这些患者广泛的细胞因子风暴对肾小球的影响，肾小球的过滤单元肾。利用研究与普通感冒有关的细胞因子风暴的五年经验引起某些形式的人类肾脏疾病的缓解，我们开发了四种新颖的“细胞因子 Covid 19细胞因子风暴的鸡尾酒”。这些细胞因子鸡尾酒包含成分特定添加剂序列中的先天和适应性免疫响应和急性影响小鼠蛋白尿。鸡尾酒中还包括固体血管紧张素转化酶2 （SACE2），是人类Covid 19的接收器的循环形式。增加的存在小鼠的肾脏疾病是足细胞表达转录因子的肌病 ZHX2可以为某些人群的疾病严重程度更高的遗传基础提供部分遗传基础。使用细胞因子部署和细胞因子接收器阻塞，我们注意到可以开发治疗相关肾脏疾病的治疗策略。在特定的目标1中，我们将在足细胞中进行机械研究与白介素4受体，白介素13受体，肿瘤坏死因子α上的细胞因子鸡尾酒α 受体和跨膜ACE2。使用基因敲除小鼠和体外研究的体内研究将使用培养的足细胞进行。在特定的目标2中，我们将研究参与Covid 19的发病机理的机制相关的肾小球疾病，尤其是肾小球病原体。缺乏肾小球的小鼠内皮整联蛋白β5表达，足细胞ZHX2表达或两者都将使用。组合整联蛋白β5表达缺乏小鼠的小鼠，那些也缺乏足细胞细胞因子受体的小鼠和肿瘤坏死因子α受体将用于研究旁分泌和自分泌反馈循环。在特定目标3中，我们将进行系统的电流细胞因子耗竭和接收器阻塞策略，还将它们结合起来开发一种新型的热范式治疗19.相关的肾小球疾病。这些部署策略可能会受益于COVID 19细胞因子风暴造成的其他最终器官损伤。