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.

1。摘要动脉粥样硬化是全球发病率和死亡率的主要原因。显然血管光滑肌肉细胞（SMC）在斑块的进展和稳定性中起着关键作用，但许多问题仍然存在关于保护性纤维帽内表型调制的SMC的来源，命运和功能和坏死核。 SMC功能的缺陷导致高血压（HTN）和血管刚度增加还通过改变容器壁内的机械信号传导来影响牙菌斑的形成和进展。虽然这些生理参数是主要的独立心血管危险因素，我们知道很少关于它们的发展，相互关系或促进动脉粥样硬化的机制。我们先前已经表明，SMC选择性RHO特异性间隙GRAF3降低了小鼠的血压和人类通过限制Rhoa依赖性SMC收缩性在抗性小动脉中，然后继续识别 RS604723作为该基因中BP相关基因座中的因果变体。我们最近的数据表明 GRAF信号传导是动脉保护性的，并抑制了收缩和细胞外基质基因的表达这种驱动血管僵硬以及促炎和促钙化基因程序有助于动脉粥样硬化的斑块发育和破裂。该提案的总体目标是评估大型且多样化的心血管疾病患者的心血管结局的GRAF3基因型人口，直接衡量格拉夫信号对动脉粥样硬化和血管僵硬的贡献，并利用我们对GRAF分子内相互作用的理解来识别GRAF激活化合物对于治疗HTN和动脉粥样硬化疾病可能很有用。