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的最常见事件，例如最小变化疾病，局灶性和节段性肾小球硬化是普通感冒。疾病的治疗继电器是一个涉及糖皮质激素和其他免疫抑制剂的漫长过程，有些是其中具有多系统毒性。我们假设继电器是由“细胞因子风暴”引起的遵循常见的冷病毒（如鼻病毒）感染。设计了“细胞因子鸡尾酒” 在小鼠中单次静脉注射后，可溶性鼻病毒受体并诱导急性蛋白尿 Podocyte ZHX2表达低，MCD和FSGS患者的共同特征。这种细胞因子鸡尾酒包括必要的先天和适应性免疫响应的组成部分足以诱导急性蛋白尿。排除任何成员的细胞因子鸡尾酒或注射个别成员不会诱发蛋白尿。在此提案中，我们将制定理论策略，以防止肾小球疾病缓解一种普通感冒，通过在细胞因子风暴中耗尽固体细胞因子，或阻止其接收器肾小球。在AIM 1中，将对足细胞中的细胞因子耗竭或接收器阻塞进行研究，并且鉴定的接收器依赖和独立机制。在AIM 2中，内皮细胞和弥赛亚细胞中细胞因子耗竭或受体阻塞的研究将是进行了，并确定了接收器依赖和独立机制。在AIM 3中，将细胞因子部署与接收器阻塞结合的治疗策略将是发达。