Covid-19 induced worsening of glomerular diseases

Covid-19 导致肾小球疾病恶化

• 批准号: 10655140
• 负责人: Camille Emilie Adeline Mace
• 金额: $ 34.76万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655140
• 关键词: 2019-nCoV; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adriamycin PFS; Albuminuria; Animal Model; Antibodies; COVID-19; COVID-19 complications; COVID-19 cytokine storm; COVID-19 diagnosis; COVID-19 impact; COVID-19 patient; COVID-19 risk; COVID-19 treatment; CXCL5 gene; Chronic Kidney Failure; Clinical Research; Complex; Creatinine; Data; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Outcome; Dose; Endothelium; Focal and Segmental Glomerulosclerosis; Goals; Heart Injuries; Histology; Hospitalization; Human; Hypersensitivity; IL-13Ralpha1; IL8RB gene; Infection; Inflammatory; Injections; Injury; Injury to Kidney; Interleukin-13; Interleukin-4; Kidney; Kidney Diseases; Knock-out; Mediating; Modeling; Morphology; Mus; Obesity; Pathway interactions; Patients; Persons; Plasma; Proteins; Proteinuria; Rattus; Renal function; Renal glomerular disease; Respiratory Tract Infections; Risk Factors; Rodent; Role; SARS-CoV-2 infection; Sepsis; Serum; Signal Pathway; System; Systemic disease; TNF gene; TNFRSF1A gene; Therapeutic; VEGFA gene; World Health Organization; acute liver injury; chemokine; coronavirus disease; cytokine; cytokine release syndrome; db/db mouse; diabetic rat; improved; improved outcome; mortality; novel therapeutic intervention; older patient; pandemic disease; podocyte; post SARS-CoV-2 infection; prevent; receptor; severe COVID-19; tumor

Summary / Abstract (max 30 lines): SARS-CoV-2 is a respiratory tract infection associated with an extensive cytokine storm. Focal and segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) are established risk factors for COVID-19 complications. Whereas both diseases can be exacerbated under cytokine storm conditions, the effect of COVID- 19 associated cytokine storm on the course of established FSGS and DN is not clear. We expect FSGS and DN to be worsened after COVID-19 infection. Based on human observational data, we generated multiple cytokine cocktails to mimic the COVID-19 cytokine storm, and showed that they cause multisystem injury when injected in rodents at high dose (severe COVID-19 in patients), and worsen kidney injury at low dose (mild COVID-19 in patients). Studying the effect of COVID-19 cytokine storm in animal models of glomerular disease will allow a better understanding of the impact of COVID-19 on patient with existing disorders. Furthermore, neutralizing the cytokine storm could potentially improve the outcome of hospitalized COVID-19 patients and prevent worsening of kidney function by using a combination of receptor blockage and cytokine depletion In Specific Aim 1, the applicant will study worsening of glomerular disease and chronic kidney disease due to FSGS and DN after induction of COVID-19 like cytokine storm. In Specific Aim 2, the applicant will assess the impact of allergy pathway cytokines IL-4 and IL-13, and inflammatory pathway cytokine TNF-α, and chemokine CXCL5 released during COVID-19 respiratory infection on pre-existing glomerular diseases. In Specific Aim 3, the applicant will treat COVID-19 related worsening of glomerular disease and chronic kidney disease FSGS and DN by depletion or blockage of the cytokine storm.

摘要/摘要（最多30行）： SARS-CoV-2是一种与广泛的细胞因子风暴相关的呼吸道感染。局灶性和节段性 肾小球硬化（FSGS）和糖尿病肾病（DN）是COVID-19的既定风险因素 并发症尽管这两种疾病在细胞因子风暴条件下都可能加重，但COVID-19的影响可能与细胞因子风暴有关。 19相关的细胞因子风暴在已建立的FSGS和DN过程中的作用尚不清楚。我们期望FSGS和DN 在COVID-19感染后恶化。基于人类的观察数据，我们产生了多种细胞因子， 鸡尾酒来模拟COVID-19细胞因子风暴，并表明它们在注射时会导致多系统损伤。 在啮齿类动物中，高剂量（患者严重的COVID-19），低剂量（患者轻度的COVID-19） 患者）。研究COVID-19细胞因子风暴在肾小球疾病动物模型中的作用将允许 更好地了解COVID-19对现有疾病患者的影响。此外， 细胞因子风暴可能会改善住院COVID-19患者的预后并防止恶化 通过结合受体阻断和细胞因子清除来改善肾功能 在具体目标1中，申请人将研究肾小球疾病和慢性肾脏疾病的恶化， 诱导COVID-19样细胞因子风暴后的FSGS和DN。 在具体目标2中，申请方将评估过敏途径细胞因子IL-4和IL-13的影响， COVID-19呼吸道感染期间释放的炎症途径细胞因子TNF-α和趋化因子CXCL 5 已经存在的肾小球疾病 在具体目标3中，申请人将治疗与COVID-19相关的肾小球疾病和慢性肾脏疾病恶化 疾病FSGS和DN通过消耗或阻断细胞因子风暴。