Atheroprotection by smooth muscle selective RhoGAPs

平滑肌选择性 RhoGAP 的动脉粥样硬化保护作用

• 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
• 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

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 动脉粥样硬化是世界范围内发病率和死亡率的主要原因。很明显，血管通畅 肌肉细胞(SMC)在斑块的进展和稳定性中起着关键作用，但仍有许多问题 关于保护性纤维帽内表型调制的SMC的来源、去向和功能 和坏死核。导致高血压(HTN)和血管僵硬增加的SMC功能缺陷 也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，我们知道的令人惊讶地很少 关于它们的发展，它们的相互关系，或它们促进动脉粥样硬化的机制。 我们之前已经证明，SMC选择性的Rho特异性GAP，GRAF3，可以降低小鼠的血压 通过限制RhoA依赖的SMC在阻力小动脉上的收缩能力 Rs604723作为该基因中BP相关基因座的因果变异。我们最近的数据表明 GRAF信号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，以及促进炎症和钙化的基因程序 动脉粥样硬化斑块的形成和破裂。这项提案的总体目标是评估 GRAF3基因对大型、多样化心血管疾病患者心血管结局的影响 为了直接测量GRAF信号在动脉粥样硬化和血管硬化中的作用， 并利用我们对Graf分子内相互作用的理解来鉴定Graf激活化合物 可能对治疗HTN和动脉粥样硬化性疾病有用。