Covid 19 cytokine storm

Covid 19细胞因子风暴

• 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
• 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

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.

摘要 COVID 19大流行与高达40%的蛋白尿发生相关 住院病人。肾脏疾病的主要表现很可能与 这些患者中广泛的细胞因子风暴对肾小球的影响，肾小球的过滤单位， 肾利用五年来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，我们开发了四种新的“细胞因子 COVID 19细胞因子风暴的鸡尾酒模型。这些细胞因子混合物含有 先天性和适应性免疫反应在一个特定的累加序列，并诱导急性 小鼠白蛋白尿。鸡尾酒中还包括可溶性血管紧张素转换酶2 （sACE2），一种人类COVID 19受体的循环形式。存在加剧 足细胞表达转录因子的亚型小鼠肾脏疾病 Zhx2可能为选择人群中疾病的严重程度提供了部分遗传基础。 使用细胞因子耗竭和细胞因子受体阻断，我们注意到， 治疗COVID相关肾病的治疗策略。 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上的细胞因子混合物 受体和跨膜ACE2。使用基因敲除小鼠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COVID 19发病机制 相关肾小球疾病，尤其是塌陷性肾小球病。肾小球缺陷小鼠 将使用内皮整合素β5表达、足细胞Zhx 2表达或两者。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受体将用于旁分泌和自分泌反馈的研究 循环 在具体目标3中，我们将进行系统性电流细胞因子清除和受体阻断 策略，并结合使用它们来开发一种新的治疗模式， 治疗COVID 19相关肾小球疾病。很可能，这些消耗战略将 有益于COVID 19细胞因子风暴引起的其他终末器官损伤。