The role of ICOSL in renal protection

ICOSL在肾脏保护中的作用

基本信息

批准号：
10368112
负责人：
Eunsil Hahm
金额：
$ 36.7万
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：
2021-03-08 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368112
关键词：
Acute Animal Model Animals Antihypertensive Agents Behavior Binding Cells Cilengitide Clinical Clinical Treatment Clinical Trials Complex Data Defense Mechanisms Development Diabetic Nephropathy Disease Disease Progression Drug Kinetics Endothelial Cells Event Focal Segmental Glomerulosclerosis Foot Process Glioblastoma Half-Life Hour Human Immunologics In Vitro Injections Injury Injury to Kidney Integrin Binding Integrin alphaVbeta3 Integrins Interleukin-2 Kidney Kidney Diseases Kidney Failure Kinetics Knockout Mice Ligands Link Measures Mechanical Stress Mediating Molecular Morphology Oxidative Stress Pathogenesis Pathologic Pathologic Processes Pathway interactions Physiological Proteinuria Publishing RGD (sequence)Recombinants Regulation Renal function Renal glomerular disease Role Signal Transduction Specificity T-Cell Activation Testing Therapeutic Time Tissues Wild Type Mouse Work antagonist base cell type design glomerular endothelium improved in vivo inducible gene expression knockout animal mesangial cell nephrogenesis novel novel therapeutics podocyte receptor response success targeted treatment therapeutic evaluation

项目摘要

Project Summary/Abstract Glomerular injury leads to proteinuric kidney diseases that often progress to renal failure. Despite advances in our understanding of the pathogenesis of glomerular disease, current treatment relies heavily on immunosuppressive or anti-hypertensive drugs and specific treatments are still lacking. Regardless of the underlying cause, one early and unifying event in glomerular injury is a morphological change in podocytes called foot process (FP) effacement. Activation of αvβ3 integrin on podocytes is linked to early pathological processes leading to FP effacement and the subsequent induction of proteinuria in several glomerular diseases, including FSGS and DN. Conversely, blocking of αvβ3 activation significantly reduces proteinuria and subsequent disease progression in animal models of FSGS and DN. However, there is currently no clinically successful approach designed to target αvβ3 integrin. We recently discovered a novel role for inducible co-stimulator ligand (ICOSL) in the protection against early glomerular injury (Koh et al., JCI, 2019). Glomerular ICOSL expression increases in early stages of human FSGS and DN, followed by a drastic decline at later stages. ICOSL deficient animals are more susceptible to kidney injury and severe proteinuria, and can be rescued by recombinant ICOSL injection. ICOSL’s RGD motif is critically important for binding to activated αvβ3 as well as its protective function. Despite this important discovery that ICOSL contributes to kidney protection, more detailed mechanistic studies are necessary to fully understand the renoprotective behavior of ICOSL as a regulator of αvβ3 integrin and to develop targeted therapies. Based on our published and preliminary data, we hypothesize that elevated ICOSL expression is a mechanism launched by podocytes as an endogenous defensive response to limit progressive kidney injury by counterbalancing the harmfully excessive activation of αvβ3 integrin. To test this hypothesis, we will precisely define the essential temporal and spatial regulation of ICOSL expression necessary to deploy its protective action (Aim 1), determine how ICOSL achieves renoprotection (Aim 2), and explore its therapeutic potential (Aim 3). Our studies will be essential steps in moving toward successful development of novel specific therapeutics for αvβ3 integrin-mediated glomerular diseases.

项目概要/摘要尽管在这方面取得了进展，但肾小球损伤会导致蛋白尿性肾病，并常常进展为肾衰竭。我们对肾小球疾病发病机制的了解，目前的治疗很大程度上依赖于无论如何，仍然缺乏免疫抑制或抗高血压药物和特异性治疗。根本原因是，肾小球损伤的一个早期且统一的事件是足细胞的形态变化足细胞上 αvβ3 整合素的激活与早期病理相关。导致 FP 消失并随后在多个肾小球中诱导蛋白尿的过程疾病，包括 FSGS 和 DN 脱机，阻断 αvβ3 激活可显着减少蛋白尿。然而，目前尚无 FSGS 和 DN 动物模型中的后续疾病进展。旨在针对 αvβ3 整合素的临床成功方法。我们最近发现了诱导共刺激配体 (ICOSL) 在预防早期肾小球损伤（Koh et al., JCI, 2019）。人类FSGS和DN随后急剧下降，后期ICOSL缺陷的动物较多。易出现肾损伤和严重蛋白尿，可通过注射重组ICOSL来挽救。尽管如此，ICOSL 的 RGD 基序对于与激活的 αvβ3 的结合及其保护功能至关重要。 ICOSL 有助于肾脏保护这一重要发现，更详细的机制研究正在有必要充分了解 ICOSL 作为 αvβ3 整合素调节剂的肾脏保护行为，并开发靶向疗法。根据我们已发表的初步数据，我们勇敢地认为 ICOSL 表达升高是一个足细胞启动的机制作为内源性防御反应，通过以下方式限制进行性肾损伤：平衡 αvβ3 整合素的有害过度激活为了检验这一假设，我们将精确地进行验证。定义 ICOSL 表达的基本时间和空间调节，以部署其保护性行动（目标 1），确定 ICOSL 如何实现肾脏保护（目标 2），并探索其治疗潜力（目标 3）。我们的研究将是成功开发新型特异性药物的重要步骤。 αvβ3 整合素介导的肾小球疾病的治疗。