Atheroprotection by smooth muscle selective RhoGAPs

平滑肌选择性 RhoGAP 的动脉粥样硬化保护作用

基本信息

批准号：
10540001
负责人：
Christopher P. Mack
金额：
$ 75.04万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540001
关键词：
Actins Affect Animals Apolipoprotein E Arterial Fatty Streak Atherosclerosis Atherosclerosis Risk in Communities Biochemical Biomedical Engineering Blood Vessels Cardiovascular Diseases Cardiovascular system Cell physiology Cells Cellular biology Cessation of life Clinical Cryoelectron Microscopy Cues Cultured Cells Data Defect Development Disease Outcome Epidemiology Event Extracellular Matrix Fluorescence Resonance Energy Transfer Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Genetic Variation Genotype Goals Human Hypertension Incidence Inflammatory Kidney Failure Knock-out Lead Left Lesion Libraries Light Measures Mechanics Methods Microscopy Modeling Molecular Molecular Analysis Morbidity - disease rate Mus Myocardial Infarction Necrosis Outcome Pathway interactions Patients Phenotype Physiological Play Post-Translational Protein Processing Resistance Risk Factors Role Rupture Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source Stroke Tamoxifen Testing Therapeutic United States Variant Vascular Diseases Vascular Smooth Muscle Work age related arterial stiffness arteriole atherogenesis atheroprotective base blood pressure control blood pressure reduction calcification cardiovascular risk factor causal variant design drug development experience genetic analysis genetic variant genome-wide analysis high throughput screening interdisciplinary approach intimal medial thickening mechanical signal member mortality mouse model novel novel therapeutics overexpression patient population pre-clinical prevent programs rho rho GTPase-activating protein screening single-cell RNA sequencing small molecule tool transcription factor

项目摘要

1. Summary Atherosclerosis is a leading cause of morbidity and mortality world-wide. It is clear that vascular smooth muscle cells (SMCs) play a critical role in plaque progression and stability, but many questions remain in regard to the source, fate, and function of the phenotypically modulated SMCs within the protective fibrous cap and necrotic core. Defects in SMC function that lead to hypertension (HTN) and increased vascular stiffness also affect plaque formation and progression by altering mechanical signaling within the vessel wall. Although these physiologic parameters are major independent cardiovascular risk factors, we know surprisingly little about their development, their inter-relationship, or the mechanisms by which they promote atherosclerosis. We have previously shown that the SMC-selective Rho-specific GAP, GRAF3, reduces blood pressure in mice and humans by limiting RhoA-dependent SMC contractility in resistance arterioles and went on to identify rs604723 as the causal variant within the BP-associated locus in this gene. Our more recent data indicate that GRAF signaling is atheroprotective and inhibits the expression of the contractile and extracellular matrix genes that drive vascular stiffness, and the pro-inflammatory and pro-calcification gene programs that contribute to atherosclerotic plaque development and rupture. The overall goals of this proposal are to assess the role of GRAF3 genotype on cardiovascular outcomes in a large and diverse cardiovascular disease patient population, to directly measure the contribution of GRAF signaling to atherosclerosis and vascular stiffening, and to use our understanding of GRAF intra-molecular interactions to identify GRAF-activating compounds that could be useful for treating HTN and atherosclerotic disease.

一、总结动脉粥样硬化是全世界发病和死亡的主要原因。很明显，血管通畅肌细胞（SMC）在斑块进展和稳定性中发挥着关键作用，但仍有许多问题关于保护性纤维帽内表型调节 SMC 的来源、命运和功能和坏死核心。 SMC 功能缺陷导致高血压 (HTN) 和血管僵硬度增加还通过改变血管壁内的机械信号来影响斑块的形成和进展。虽然这些生理参数是主要的独立心血管危险因素，但我们知之甚少关于它们的发展、相互关系或它们促进动脉粥样硬化的机制。我们之前已经证明 SMC 选择性 Rho 特异性 GAP GRAF3 可以降低小鼠血压和人类通过限制阻力小动脉中 RhoA 依赖性 SMC 收缩性，并继续确定 rs604723 作为该基因中 BP 相关基因座内的因果变异。我们最新的数据表明 GRAF 信号传导具有动脉粥样硬化保护作用，并抑制收缩和细胞外基质基因的表达驱动血管僵硬的促炎症和促钙化基因程序有助于动脉粥样硬化斑块的发展和破裂。该提案的总体目标是评估 GRAF3 基因型对大型且多样化的心血管疾病患者心血管结局的影响人群，直接测量 GRAF 信号对动脉粥样硬化和血管硬化的贡献，并利用我们对 GRAF 分子内相互作用的理解来识别 GRAF 激活化合物可用于治疗高血压和动脉粥样硬化疾病。