"MerTK Cleavage and Signaling in Atherosclerosis"

 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显著动脉粥样硬化的机制，然后利用这些知识设计新的治疗方法。形成该提议的基础的总体概念是斑块进展代表称为缺陷性炎症消退的病理过程。该提案是基于强有力的体外和体内数据，支持巨噬细胞（Mf）MerTK受体在分辨率响应中的关键作用-一种在晚期动脉粥样硬化中出错的响应。MerTK使Mfs能够进行红细胞增多，这是动脉粥样硬化中的关键消退过程，并促进专门的促消退介质（SPM）的合成，包括脂氧素A4（LXA 4）和消退素D1（RvD 1）。此外，在炎症环境中，包括在晚期动脉粥样硬化病变中，MerTK被ADAM 17介导的裂解破坏。我们认为，这一过程损害了红细胞增多症和SPM的合成，导致了人类临床上危险的坏死性、炎症性斑块类型的进展。在该提案中，目标1将进一步探索MerTK在Mfs中发出炎症消退反应信号以及MerTK在动脉粥样硬化中裂解损害消退并促进斑块进展的假设。我们将研究MerTK信号传导与SPM合成的联系机制，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已被完全功能性抗切割Mertk取代），测试MerTK切割在缺陷性红细胞增多症、缺陷性介质合成和动脉粥样硬化斑块进展中的重要性。目的2探讨动脉粥样硬化相关因子和SPM对MerTK裂解的调节作用。我们将讨论几个假设，动脉粥样硬化相关因素如何促进ADAM 17介导的MerTK裂解，并根据新的数据，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提供基础。动脉粥样硬化血栓性血管疾病是工业化国家的主要死亡原因， 未来在防治这种疾病方面存在着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，其方式有可能通过使用促消退治疗高度转化为人类治疗。

 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.