PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype

PDGFbeta 受体激活促进 SMC 表型的动脉粥样硬化变化

基本信息

批准号：
9908167
负责人：
Gary K Owens
金额：
$ 65.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908167
关键词：
Age Alleles Anti-Inflammatory Agents Apolipoprotein E Apoptosis Arterial Fatty Streak Atherosclerosis Cause of Death Cell Count Cell Lineage Cells Clinical Collagen Development Diet Event Extracellular Matrix Foam Cells Genes Genetic Genomics Gleevec Goals Grant Hemorrhage Human Imatinib In Vitro Incidence Inflammatory Infusion procedures Interleukin-1 beta Intravenous infusion procedures Knock-out Knockout Mice Lead Lesion Lesion by Stage Lipids Mechanics Medicine Mesenchymal Mitogens Mus Myocardial Infarction Myofibroblast Nature Necrosis Pathogenesis Pharmaceutical Preparations Pharmacology Phenotype Phenylephrine Play Probability Progressive Disease Receptor Activation Receptor Signaling Research Resolution Role Rupture Signal Pathway Smooth Muscle Myocytes Stroke Tamoxifen Testing Thick Thinness Vascular Smooth Muscle Western World atheroprotective biomarker panel cell dedifferentiation cell type conditional knockout cytokine feeding in vivo indexing inhibitor/antagonist macrophage migration neutralizing antibody new therapeutic target novel novel strategies novel therapeutic intervention pluripotency receptor stem cells therapeutic target transcriptome sequencing virtual western diet

Age Alleles Anti-Inflammatory Agents Apolipoprotein E Apoptosis Arterial Fatty Streak Atherosclerosis Cause of Death Cell Count Cell Lineage Cells Clinical Collagen Development Diet Event Extracellular Matrix Foam Cells Genes Genetic Genomics Gleevec Goals Grant Hemorrhage Human Imatinib In Vitro Incidence Inflammatory Infusion procedures Interleukin-1 beta Intravenous infusion procedures Knock-out Knockout Mice Lead Lesion Lesion by Stage Lipids Mechanics Medicine Mesenchymal Mitogens Mus Myocardial Infarction Myofibroblast Nature Necrosis Pathogenesis Pharmaceutical Preparations Pharmacology Phenotype Phenylephrine Play Probability Progressive Disease Receptor Activation Receptor Signaling Research Resolution Role Rupture Signal Pathway Smooth Muscle Myocytes Stroke Tamoxifen Testing Thick Thinness Vascular Smooth Muscle Western World atheroprotective biomarker panel cell dedifferentiation cell type conditional knockout cytokine feeding in vivo indexing inhibitor/antagonist macrophage migration neutralizing antibody new therapeutic target novel novel strategies novel therapeutic intervention pluripotency receptor stem cells therapeutic target transcriptome sequencing virtual western diet

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项目摘要

Atherosclerosis is a progressive disease that is a leading cause of death in the Western world. Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4 or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has been generally appreciated. Key findings include our showing that: 1) >80% of SMC-derived cells within advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC-derived cells within both advanced mouse and human lesions lack detectable SMC markers and have activated markers of MФs; and 3) SMC can have major beneficial or detrimental effects on lesion pathogenesis depending on the nature of their phenotypic transitions. Thus, there is a critical need to identify factors and mechanisms that promote beneficial changes in SMC phenotype. Studies in this proposal will test the overall hypothesis that PDGFβR-dependent changes in SMC phenotype are atheroprotective and that augmentation of the PDGFβR signaling pathway should be one of the primary therapeutic targets for treating advanced atherosclerosis. This hypothesis will be tested in two specific aims. Aim 1 will test the hypothesis that PDGFβR- dependent transitions in SMC phenotypic play a critical role in the development and progression of atherosclerosis. Aim 1a will extend our initial studies showing that SMC specific conditional PDGFβR KO at 6-8 weeks of age followed by 18 weeks of Western diet (WD) resulted in BCA lesions that were larger but virtually lacking SMC to include rigorous analysis of indices of plaque stability and mechanisms for reductions in SMC number within lesions. Aim 1b will test the hypothesis that SMC-specific conditional KO of PDGFβR results in detrimental transitions in SMC phenotype including increased numbers of SMC-derived Lgals3+ foam cells (SMC-FC) and reduced numbers of SMC derived myofibroblasts (SMC-MF) within the fibrous cap. Aim 2 will test the hypothesis that PDGFβR-signaling pathways confer atheroprotective effects within advanced atherosclerotic lesions at least in part through inducing favorable changes in SMC phenotype. Studies will test how SMC-specific or global genetic or pharmacologic inhibition (Aims 2a-2c) or augmentation (infusion of rPDGF- DD, Aim 2d) of PDGFβR signaling in Western diet fed ApoE-/- mice with advanced atherosclerotic lesions impacts overall lesion pathogenesis, indices of plaque stability, SMC phenotypic transitions, and the incidence of plaque rupture. Results may lead to development of novel therapeutic approaches for reducing late stage clinical complications of atherosclerosis by inducing SMC to undergo beneficial changes in phenotype-function that promote formation of a thicker and mechanically more stable fibrous cap, thus reducing the probability of plaque rupture and a possible MI or stroke.

动脉粥样硬化是一种进行性疾病，是西方世界中死亡的主要原因。值得注意的是尽管进行了数十年的研究，但关于平滑肌细胞的作用仍然存在主要的歧义（SMC）在病变发病机理中以及控制斑块稳定性和斑块破裂概率的机制可能具有心肌梗塞（MI）或中风。一般的教条是SMC主要参与迟到不是早期病变，它们的主要作用是通过纤维形成的作用帽。但是，我们的实验室最近的自然医学研究涉及简单的SMC特异性谱系跟踪干细胞多能基因，Oct4或KLF4的敲除（KO）提供了令人信服的证据证明SMC 在病变发病机理中起着比普遍理解的更大的作用。关键发现包括我们表明：1）> 80％的SMC衍生细胞在APOE - / - 小鼠的高级病变中缺乏可检测的表达式典型的SMC标记； 2）缺乏高级小鼠和人类病变中SMC衍生细胞的30-40％可检测的SMC标记并激活了MOS的标记； 3）SMC可以具有重大有益或根据其表型过渡的性质，对病变发病机理的有害作用。那是识别促进SMC表型有益变化的因素和机制的关键需求。对此进行了研究提案将检验总体假设，即SMC表型中PDGFβR依赖性变化是动脉保护性的，并且 PDGFβR信号通路的增强应该是治疗的主要治疗靶标之一高级动脉粥样硬化。该假设将以两个具体的目的进行检验。 AIM 1将检验PDGFβR-的假设 SMC表型中的依赖过渡在动脉粥样硬化的发展和发展中起关键作用。目的 1A将延长我们的初步研究，表明SMC特异性有条件的PDGFβRKO在6-8周龄，然后是18 西部饮食（WD）数周导致BCA病变较大，但实际上缺乏SMC，包括严格的分析病变内SMC数量减少的牙菌斑稳定性指标和机制。 AIM 1B将检验假设 PDGFβR的SMC特异性条件KO导致SMC表型的有害转变，包括增加 SMC衍生的LGALS3+泡沫细胞（SMC-FC）和SMC数量减少的SMC数量（SMC-MF）的数量减少在纤维帽内。 AIM 2将检验以下假设：PDGFβR信号途径会议会议动脉保护作用在高级动脉粥样硬化病变中，至少部分通过SMC表型的有利变化而部分。研究将测试SMC特异性或全球遗传或药物抑制（AIMS 2A-2C）或增强如何（输注RPDGF-） DD，pDGFβR信号的AIM 2d）在西部饮食中喂养的APOE - / - 具有晚期动脉粥样硬化病变的总体影响病变发病机理，斑块稳定性指标，SMC表型过渡和斑块破裂的入射。结果可能导致开发新的治疗方法，以减少动脉粥样硬化的晚期临床并发症通过诱导SMC在表型功能上经历有益的变化，以促进较厚和较厚的形成机械上更稳定的纤维帽，从而降低了斑块破裂的概率和可能的MI或中风。