The role of ICOSL in renal protection

ICOSL在肾脏保护中的作用

• 批准号: 10553240
• 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
• 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/10553240
• 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 and 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; Predisposition; 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; 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.

项目总结/摘要 肾小球损伤导致蛋白尿性肾病，通常进展为肾衰竭。尽管取得了进展， 我们对肾小球疾病发病机制的理解，目前的治疗严重依赖于 免疫抑制或抗高血压药物和特异性治疗仍然缺乏。无论 肾小球损伤的一个早期统一事件是足细胞的形态学改变 称为足突消失。足细胞上αvβ3整合素的活化与早期病理性 导致FP消失和随后诱导蛋白尿的过程在几个肾小球 包括FSGS和DN。相反，阻断αvβ3的激活能显著减少蛋白尿 和随后的疾病进展。但目前尚无 设计用于靶向αvβ3整联蛋白的临床成功方法。 我们最近发现了一种新的作用，诱导共刺激配体（ICOSL）的保护， 早期肾小球损伤（Koh等，JCI，2019）。肾小球ICOSL表达在糖尿病早期增加， 人FSGS和DN，随后在后期急剧下降。ICOSL缺陷动物更多 易发生肾损伤和严重蛋白尿，可通过重组ICOSL注射液进行挽救。 ICOSL的RGD基序对于结合活化的αvβ3及其保护功能至关重要。尽管 这一重要发现，ICOSL有助于肾脏保护，更详细的机制研究是 有必要充分了解ICOSL作为αvβ3整合素调节剂的肾保护行为， 发展靶向治疗。 基于我们已发表的和初步的数据，我们假设升高的ICOSL表达是一个重要的因素。 足细胞启动的一种机制，作为内源性防御反应，以限制进行性肾损伤， 平衡αvβ3整联蛋白的有害过度活化。为了验证这一假设，我们将 定义必要的时间和空间调控ICOSL表达部署其保护性 作用（目标1），确定ICOSL如何实现肾保护（目标2），并探索其治疗潜力 (Aim（3）第三章。我们的研究将是迈向成功开发新的具体的重要步骤。 αvβ3整联蛋白介导的肾小球疾病的治疗剂。