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Soluble mediators of relapse

复发的可溶性介质

基本信息

批准号：
10396046
负责人：
Sumant Singh Chugh
金额：
$ 52.73万
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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396046
关键词：
ANGPTL4 gene Acute Albuminuria Alleles Animal Disease Models Antibodies BALB/cJ Mouse Binding Body Surface Buffaloes CRISPR/Cas technology Cell Nucleus Cell membrane Cells Common Cold Common Cold Virus Cytokine Receptors Dependence Development Disease Dissociation Down-Regulation Endothelial Cells Ephrin-B1 Event Exclusion Focal Segmental Glomerulosclerosis Gene Proteins Genomics Glucocorticoids Histology Hodgkin Disease Human IL-13Ralpha1 Inbred BALB C Mice Individual Infection Injections Intercellular adhesion molecule 1 Interferon Type II Interferons Interleukin 4 Receptor Interleukin-10 Interleukin-2 Interleukin-6 Kidney Link Mediating Mediator of activation protein Modeling Mus Myristica fragrans Nasal Epithelium Natural Immunity Nature Nuclear Patients Pharmaceutical Preparations Process Proteins Proteinuria Rattus Recurrent disease Relapse Renal glomerular disease Rhinitis Rhinovirus Signal Pathway Stimulus TNF gene Therapeutic Toxic effect Untranslated RNA Variant Zinc Fingers adaptive immune response adaptive immunity cytokine cytokine release syndrome design factor A glutamyl aminopeptidase in vivo insertion/deletion mutation intravenous injection member mesangial cell novel novel strategies podocyte prevent receptor synergism targeted treatment transcription factor treatment strategy

项目摘要

Abstract The most common event preceding relapse of primary glomerular diseases like Minimal Change Disease and Focal and Segmental Glomerulosclerosis is the common cold. Treatment of disease relapse is a lengthy process involving glucocorticoids and other immunosuppressive medications, some of which have multi-system toxicity. We hypothesized that relapse is induced by a “cytokine storm” that follows infection by common cold viruses like Rhinovirus. A “cytokine cocktail” was designed around the soluble Rhinovirus receptor and induces acute albuminuria after single intravenous injection in mice with low podocyte Zhx2 expression, a common feature in MCD and FSGS patients. This cytokine cocktail comprises of components of the innate and adaptive immune response that are necessary and sufficient to induce acute albuminuria. Exclusion of any member from the cytokine cocktail, or injection of individual members does not induce albuminuria. In this proposal, we will develop therapeutic strategies to prevent relapse of glomerular diseases after a common cold, by depleting soluble cytokines in the cytokine storm, or blocking their receptors in the glomerulus. In Aim 1, studies on cytokine depletion or receptor blockage in the podocyte will be conducted, and receptor dependent and independent mechanisms identified. In Aim 2, studies on cytokine depletion or receptor blockage in endothelial and mesangial cells will be conducted, and receptor dependent and independent mechanisms identified. In Aim 3, a therapeutic strategy that combines cytokine depletion with receptor blockage will be developed.

抽象的原发性肾小球疾病复发前最常见的事件，例如微小变化疾病和局灶性和节段性肾小球硬化症是普通感冒。疾病治疗复发是一个漫长的过程，涉及糖皮质激素和其他免疫抑制药物，有些其中具有多系统毒性。我们假设复发是由“细胞因子风暴”引起的，感染鼻病毒等普通感冒病毒后。 “细胞因子鸡尾酒”的设计围绕可溶性鼻病毒受体并在小鼠单次静脉注射后诱导急性蛋白尿足细胞 Zhx2 表达低，这是 MCD 和 FSGS 患者的共同特征。这种细胞因子鸡尾酒由先天性和适应性免疫反应的必要组成部分组成足以诱发急性蛋白尿。将任何成员排除在细胞因子鸡尾酒或注射之外个别成员不会引起蛋白尿。在本提案中，我们将制定治疗策略，以预防肾小球疾病术后复发普通感冒，通过消耗细胞因子风暴中的可溶性细胞因子，或阻断其受体肾小球。在目标 1 中，将进行足细胞细胞因子消耗或受体阻断的研究，以及确定了受体依赖性和非依赖性机制。在目标 2 中，将研究内皮细胞和系膜细胞中的细胞因子耗竭或受体阻断进行，并确定了受体依赖性和独立机制。在目标 3 中，将细胞因子耗竭与受体阻断相结合的治疗策略将是发达。