C-Kit in Atherosclerosis

C-Kit 在动脉粥样硬化中的应用

基本信息

批准号：
9319457
负责人：
Roberto Irenardo Vazquez Padron
金额：
$ 8.21万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319457
关键词：
American Aorta Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Behavior Blood Vessels C-KIT Gene Carotid Arteries Cause of Death Cell Culture Techniques Cells Cholesterol Chronic Disease Clinical Complex Coronary Arteriosclerosis Development Disease Disease Progression Encapsulated Endothelium Enterobacteria phage P1 Cre recombinase Equilibrium Genes Genetic Transcription Genetically Engineered Mouse Goals High Fat Diet Impairment Inflammation Inflammatory Invaded Knockout Mice Knowledge Lesion Life Style Link Lipids MAP Kinase Gene Mediating Molecular Mus Muscle Cells Mutant Strains Mice Nuclear Outcome Study Pathologic Peripheral arterial disease Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Protein Dephosphorylation Proto-Oncogene Protein c-kit Risk Role Rupture Serum Response Factor Signal Transduction Smooth Muscle Smooth Muscle Myocytes Specificity Stem Cell Factor Symptoms Tamoxifen Testing Translating Tyrosine United States Vascular Smooth Muscle cadherin 5 cerebrovascular design disability feeding gain of function human disease hypercholesterolemia in vivo inhibitor/antagonist loss of function mouse model myocardin new therapeutic target novel novel therapeutic intervention prevent public health relevance receptor reconstitution transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of death and illness in the United States despite all advances in lipid- lowering drugs and lifestyle changes designed to reduce cholesterol levels. Atherosclerosis is a chronic disease that causes accumulation of plaques in the arterial walls. Smooth muscle cells (SMCs) that migrate from the media after phenotypic switching significantly contribute to atherosclerosis and plaque stability. However, the molecular mechanisms responsible for SMC phenotypic modulation in disease development still remain unclear. Consequently, we hypothesize that c-Kit signaling stabilizes the SMC contractile phenotype in arterial walls, which controls the progression of the disease in early atherosclerosis and decreases the risk of plaque rupture in advanced lesions. We support the hypothesis with preliminary studies that demonstrate: 1) the expression of c-Kit in healthy and diseased human and mouse aortas, 2) the role of c-Kit in SMC phenotypic switching, 3) increased systemic atherosclerosis in hyperlipidemic mice with impaired SCF or c-Kit functions, and 4) increased risk for vulnerable plaque rupture in c-Kit deficient mice . We will prove our hypothesis in three specific aims. In aim 1 we propose to test whether c-Kit loss or gain-of-function in SMCs alters atherosclerosis development in hyperlipidemic mice. We will make use of a novel genetically engineered mouse and a newly designed inducible lentivector to inactivate or activate the c-Kit gene in arterial SMCs. In aim 2 we will examine the molecular mechanisms by which c-Kit maintains the contractile phenotype in SMCs. We will use culture cells from c-Kit conditional knockout mice to demonstrate the relevance of the c- Kit/PI3K/Akt signaling axis and DUSP mediated dephosphorylation of MAPK in maintaining the transcription of SMC contractile genes. Finally, in aim 3 we will investigate the impact of altering vascular c-Kit signaling in vascular inflammation and atherosclerotic plaque rupture in vivo. We will evaluate spontaneous plaque rupture in HFD fed conditional mice after tamoxifen feeding to inactivate the c-Kit gene in the plaque. Together, these studies will advance our knowledge about the role of c-Kit in atherosclerosis and will furnish new therapeutic targets to prevent and eventually mitigate the devastating effects of atherosclerosis.

描述（由申请人提供）：尽管降脂药物和生活方式的改变旨在降低胆固醇水平，但动脉粥样硬化是一种导致动脉斑块积聚的慢性疾病，但动脉粥样硬化是美国死亡和疾病的主要原因。表型转换后从介质中迁移的平滑肌细胞 (SMC) 显着促进动脉粥样硬化和斑块稳定性。然而，负责 SMC 表型调节的分子机制。在疾病发展中的研究仍不清楚，我们致力于 c-Kit 信号稳定动脉壁中的 SMC 收缩表型，从而控制早期动脉粥样硬化的疾病进展并降低晚期病变中斑块破裂的风险。初步研究表明：1) c-Kit 在健康和患病的人和小鼠主动脉中的表达，2) c-Kit 在 SMC 表型转换中的作用，3) 全身性增加SCF 或 c-Kit 功能受损的高脂血症小鼠出现动脉粥样硬化，4) c-Kit 缺陷小鼠的易损斑块破裂风险增加。我们将在三个具体目标中证明我们的假设。在目标 1 中，我们建议测试 c-Kit 是否存在。 SMC 功能的丧失或获得会改变高脂血症小鼠的动脉粥样硬化发展。我们将利用新型基因工程小鼠和新设计的诱导慢载体来实现这一目标。失活或激活动脉 SMC 中的 c-Kit 基因在目标 2 中，我们将研究 c-Kit 在 SMC 中维持收缩表型的分子机制。 c-Kit/PI3K/Akt 信号轴和 DUSP 介导的 MAPK 去磷酸化在维持 SMC 收缩基因转录中的作用最后，在目标 3 中，我们将研究改变的影响。体内血管炎症和动脉粥样硬化斑块破裂中的血管 c-Kit 信号传导我们将评估 HFD 喂养条件小鼠在喂食他莫昔芬以灭活斑块中的 c-Kit 基因后的自发斑块破裂。 c-Kit 在动脉粥样硬化中的作用，并将提供新的治疗靶点，以预防并最终减轻动脉粥样硬化的破坏性影响。