"MerTK Cleavage and Signaling in Atherosclerosis"

“动脉粥样硬化中的 MerTK 裂解和信号转导”

• 批准号: 9120607
• 负责人: Ira A Tabas
• 金额: $ 50.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120607
• 关键词: Acute; Address; Affect; Apolipoprotein E; Apoptotic; Arachidonate 5-Lipoxygenase; Arterial Fatty Streak; Atherosclerosis; Biological; Blood coagulation; Cause of Death; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Cytoplasmic Tail; Data; Defect; Developed Countries; Disease; Economic Burden; Event; FPR2 gene; Feedback; Future; Genetic; Goals; Heart Diseases; Heart Research; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integrins; Knowledge; Lesion; Leukotriene B4; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; M cell; Mediating; Mediator of activation protein; Methods; Minority; Modeling; Morbidity - disease rate; Mus; Mutation; Myocardial Infarction; Necrosis; Nuclear; Pathologic Processes; Peptides; Phagocytosis; Phospholipids; Process; Property; Publishing; Regulation; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Vascular Diseases; Work; base; clinically relevant; clinically significant; combat; design; fascinate; feeding; high risk; in vivo; interest; lipoxin A4; macrophage; mortality; novel therapeutics; oxidized low density lipoprotein; pre-clinical; prevent; public health relevance; receptor; repaired; response; tool; western diet

 DESCRIPTION (provided by applicant): A critical goal in heart research is to elucidate the mechanisms that promote clinically significant atherosclerosis and then use this knowledge to design novel therapies. The overarching concept that a form the basis of this proposal is that plaque progression represents a pathologic process called defective inflammation resolution. The proposal is based on strong in vitro and in vivo data supporting a critical role for the macrophage (Mf) MerTK receptor in the resolution response--a response that goes awry in advanced atherosclerosis. MerTK enables Mfs to carry out efferocytosis, a critical resolving process in atherosclerosis, and to promote the synthesis of specialized pro-resolving mediators (SPMs), including lipoxin A4 (LXA4) and resolvin D1 (RvD1). Moreover, in inflammatory settings including in advanced atherosclerotic lesions, MerTK is destroyed by ADAM17-mediated cleavage. We propose that this process compromises both efferocytosis and the synthesis of SPMs, leading to the progression of the type of necrotic, inflammatory plaques that, in humans, are clinically dangerous. In this proposal, Aim 1 will further explore the hypothesis that MerTK signals an inflammation resolution response in Mfs, and that MerTK cleavage in atherosclerosis compromises resolution and promotes plaque progression. We will investigate the mechanisms linking MerTK signaling to SPM synthesis and then test the importance of MerTK cleavage in defective efferocytosis, defective mediator synthesis, and plaque progression in atherosclerosis by comparing WD-fed MertkWT Ldlr-/- mice with MertkCR Ldlr-/- mice, which is a unique model in which endogenous Mertk has been replaced by a fully functional cleavage-resistance Mertk. Aim 2 will explore the regulation of MerTK cleavage by athero-relevant factors and SPMs, both in vitro and in atherosclerosis. We will address several hypotheses as to how athero-relevant factors promote ADAM17-mediated MerTK cleavage and, based on new data, how SPMs suppress MerTK cleavage. At the conclusion of this project, we hope to have elucidated new mechanistic links between inflammation resolution and atherosclerosis, which could provide the basis for new drugs that block plaque progress in high-risk humans. Atherothrombotic vascular disease is the leading cause of death in the industrialized world, with global spread predicted for the future. Important mechanistic and therapeutic gaps exist in combatting this disease. This proposal will study mechanisms that promote atherosclerosis progression in a manner that has the potential to be highly translatable to human therapy through the use of pro-resolving therapy.

 描述（由申请人提供）：心脏研究的一个关键目标是阐明促进临床上显着的动脉粥样硬化的机制，然后利用这些知识设计新的疗法。该提议的基础是，斑块进展代表一种称为缺陷性炎症消退的病理过程。该提议基于强有力的体外和体内数据，支持巨噬细胞 (Mf) MerTK 受体在消退反应中发挥关键作用，这种反应在晚期动脉粥样硬化中会出错。 MerTK 使 Mfs 能够进行胞吞作用（动脉粥样硬化中的一个关键溶解过程），并促进专门的促溶解介质 (SPM) 的合成，包括脂氧素 A4 (LXA4) 和溶解素 D1 (RvD1)。此外，在炎症环境中，包括晚期动脉粥样硬化病变中，MerTK 会被 ADAM17 介导的裂解破坏。我们认为，这一过程会损害胞吞作用和 SPM 的合成，导致坏死性炎症斑块类型的进展，这对人类来说具有临床危险。在本提案中，目标 1 将进一步探讨这样的假设：MerTK 在 Mfs 中发出炎症消退反应信号，而动脉粥样硬化中的 MerTK 裂解会损害消退并促进斑块进展。我们将研究 MerTK 信号传导与 SPM 合成之间的联系机制，然后通过比较 WD 喂养的 MertkWT Ldlr-/- 小鼠与 MertkCR Ldlr-/- 小鼠（这是一种独特的模型，其中内源性 Mertk 已被 功能齐全的抗裂解 Mertk。目标 2 将探索动脉粥样硬化相关因子和 SPM 对体外和动脉粥样硬化中 MerTK 裂解的调节。我们将提出几个假设，即动脉粥样硬化相关因素如何促进 ADAM17 介导的 MerTK 裂解，以及基于新数据的 SPM 如何抑制 MerTK 裂解。在该项目结束时，我们希望阐明炎症消退和动脉粥样硬化之间的新机制联系，这可以为阻止高危人群斑块进展的新药物提供基础。动脉粥样硬化性血管疾病是工业化国家的首要死因，预计将在全球蔓延 未来。在对抗这种疾病方面存在重要的机制和治疗差距。该提案将研究促进动脉粥样硬化进展的机制，通过使用促解决疗法，该机制有可能高度转化为人类疗法。