Role of Ribosomal Proteins in Vascular Smooth Muscle Cell Proliferation

核糖体蛋白在血管平滑肌细胞增殖中的作用

• 批准号: 7677721
• 负责人: Elaine M Smolock
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677721
• 关键词: Address; Atherosclerosis; Basic Science; Blood Vessels; Blood flow; C3HeB/FeJ Mouse; Caliber; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cause of Death; Cell Cycle; Cell Proliferation; Clinical; Coronary; Data; Event; Figs - dietary; Functional disorder; Future; Genes; Genetic; Goals; Homeostasis; Human; Hypertension; Inflammation; Inflammatory; Interleukin-18; Investigation; Laboratories; Left; Ligation; Literature; Measurable; Mediating; Microarray Analysis; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Myocardial Infarction; Oxidative Stress; Pathway interactions; Peripheral Vascular Diseases; Phenotype; Physiological; Process; Protein Biosynthesis; Proteins; Public Health; Regulation; Research; Resistance; Ribosomal Proteins; Risk Factors; Role; SJL/J Mouse; SOD2 gene; Smooth Muscle Myocytes; Stroke; Superoxide Dismutase; Symptoms; Therapeutic; Therapeutic Agents; Training; Tumor Suppressor Proteins; Vascular remodeling; Western World; atherogenesis; base; cardiovascular disorder prevention; cell growth; cytokine; design; genetic technology; in vivo; intima media; knowledge base; mitochondrial dysfunction; mouse model; novel; protein function; public health relevance; research study; skills; vascular inflammation; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Our laboratory has developed a partial carotid ligation mouse model to investigate mechanisms involved in flow induced vascular remodeling. Phenotypic analysis of the effect of decreased blood flow in the left carotid arteries of C3HeB/FeJ (C3H/F) showed that these mice are resistant to intima formation when blood flow decreases while SJL/J are highly susceptible to intima-media thickening associated with increases in vascular smooth muscle cell (VSMC) proliferation and increased inflammation. Investigations of differences in these two strains showed that SJL/J had increased inflammatory cytokines (IL-18 and Mif1) endothelial dysfunction, decreased superoxide dismutase (SOD2) and increased nitortyrosine. Microarray analysis of carotids from sham-operated C3H/F and SJL/J mice generated a list of candidate genes that may contribute to the difference in intima phenotype seen in SJL/J compared to C3H/F. Two of the candidate genes identified were ribosomal proteins (Rpl), Rpl17 and Rpl7-like1. While several laboratories have suggested a role for Rpl's in VSMC proliferation, this topic has not been well studied. Importantly, two microarray studies of VSMC phenotypic modulation have demonstrated significant changes in Rpl's including one that also identified Rpl17. Furthermore, evidence suggests that Rpl's can act as tumor suppressors, decreasing cell proliferation. Based on our results and the supporting evidence in the literature, our major hypothesis is that Rpl function is critical in regulating strain dependent VSMC mediated intima formation. PUBLIC HEALTH RELEVANCE: Atherosclerotic cardiovascular disease is the leading cause of morbidity in the Western world with hypertension being a predominant risk factor. IMT has been well validated as an important predictor of cardiovascular disease. A clearer understanding of the pathways that regulate IMT should assist in the design of more effective therapeutic agents to reduce carotid, coronary and peripheral vascular disease. At a basic science level, investigation of the role of ribosomal protein function VSMC growth and inflammation will provide novel information regarding the molecular pathways in vascular homeostasis.

描述(由申请人提供)：我们的实验室已经建立了一个部分颈动脉结扎的小鼠模型，以研究涉及血流诱导的血管重构的机制。对C3HeB/FEJ(C3HeB/FEJ)小鼠左颈动脉血流减少的表型分析表明，当血流减少时，这些小鼠对内膜形成具有抵抗力，而SJL/J小鼠对与血管平滑肌细胞(VSMC)增殖增加和炎症增加相关的内膜中层增厚高度敏感。两株菌株的差异研究表明，SJL/J增加了炎性细胞因子(IL-18和Mif1)的内皮功能障碍，降低了超氧化物歧化酶(SOD2)，增加了硝基酪氨酸。对来自假手术的C3H/F和SJL/J小鼠颈动脉的微阵列分析产生了可能导致SJL/J和C3H/F的内膜表型差异的候选基因列表。其中两个被鉴定的候选基因是核糖体蛋白(RPL)、Rpl17和Rpl7-like 1。虽然几个实验室已经提出了RPL在VSMC增殖中的作用，但这个课题还没有得到很好的研究。重要的是，两项关于VSMC表型调节的微阵列研究已经证明了RPL的显著变化，其中一项研究也鉴定了RPL17。此外，有证据表明，RPL可以作为肿瘤抑制因子，抑制细胞增殖。基于我们的结果和文献中支持的证据，我们的主要假设是RPL功能在调节应变依赖的VSMC介导的内膜形成中起关键作用。公共卫生相关性：动脉粥样硬化性心血管疾病是西方世界发病率的主要原因，高血压是主要的危险因素。IMT已被证实是心血管疾病的重要预测指标。更清楚地了解调节IMT的途径应该有助于设计更有效的治疗药物来减少颈动脉、冠状动脉和外周血管疾病。在基础科学水平上，研究核糖体蛋白功能在VSMC生长和炎症中的作用将提供关于血管内稳态的分子途径的新信息。