The role of ICOSL in renal protection

ICOSL在肾脏保护中的作用

• 批准号: 10209294
• 负责人: Eunsil Hahm
• 金额: $ 36.63万
• 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: 2021-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209294
• 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; 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

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.

项目摘要/摘要 肾小球损伤会导致蛋白尿肾脏疾病，通常会发展为肾衰竭。尽管进步 我们对肾小球疾病发病机理的理解，当前治疗在很大程度上取决于 仍然缺乏免疫抑制或抗高血压药物和特定治疗方法。不管是什么 根本原因，肾小球损伤中的一个早期和统一事件是足细胞的形态变化 称为脚步过程（FP）能量。 αVβ3整联蛋白在足细胞上的激活与早期病理有关 导致FP能量的过程以及随后在几个肾小球中诱导蛋白尿 包括FSG和DN在内的疾病。相反，αVβ3激活的阻塞显着降低了蛋白质 以及随后的FSG和DN动物模型中的疾病进展。但是，目前没有 临床成功的方法旨在靶向αVβ3整合素。 最近，我们发现了诱导共刺激配体（ICOSL）在保护中的新作用 早期肾小球损伤（Koh等人，JCI，2019年）。肾小球ICOSL表达在早期的早期阶段增加 人类FSG和DN，随后在后期急剧下降。 ICOSL缺乏动物更多 易受肾脏损伤和严重的蛋白尿，可以通过重组ICOSL注射来挽救。 ICOSL的RGD基序对于与活化的αVβ3及其保护功能至关重要。尽管 ICOSL有助于肾脏保护的这一重要发现，更详细的机理研究是 完全理解ICOSL作为αVβ3整合素的调节剂和TO的必要条件 开发的靶向疗法。 基于我们发布的和初步数据，我们假设ICOSL表达升高是一种 足细胞发射的机制是内源性防御反应，以限制通过 平衡αVβ3整联蛋白的过量激活。为了检验这一假设，我们将精确 定义部署其受保护所必需的ICOSL表达的基本临时和空间调节 动作（AIM 1），确定ICOSL如何实现重生保护（AIM 2），并探索其治疗潜力 （目标3）。我们的研究将是朝着成功开发新颖特定的发展的重要步骤 αVβ3整联蛋白介导的肾小球疾病的治疗剂。