Non lipid-lowering statin effects mediated by PI3K

PI3K 介导的他汀类药物非降脂作用

• 批准号: 6898100
• 负责人: SUSAN A MCDOWELL
• 金额: $ 20.38万
• 依托单位: BALL STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898100
• 关键词: Adenoviridae; HMG coA reductases; apoptosis; biological signal transduction; calcium flux; cardiovascular pharmacology; cell line; cell surface receptors; coronary artery; enzyme activity; enzyme induction /repression; enzyme inhibitors; enzyme mechanism; genetic promoter element; genetic transcription; isozymes; phosphatidylinositol 3 kinase; protein tyrosine kinase; simvastatin; transfection /expression vector; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Our research focuses on the phosphoinositide 3-kinase (PI3K) family of proteins in the maintenance of cardiovascular health and in the progression of cardiovascular disease. The objective of this research proposal is to better understand intracellular signaling mechanisms and cellular consequences of 3-hydroxy-3-methylgultaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) mediated by PI3K. Specific PI3K isoforms mediate distinct functions. For example, in the heart, PI3K can stimulate both pathologic and physiologic responses and the key to this apparent discrepancy appears to be based upon which PI3K isoform is activated. The specific aims in this proposal will test the hypothesis that the stimulation of a PI3K isoform or subset of isoforms leads to distinct cell-signaling events in response to simvastatin that are independent of lipid-lowering. The approach will be to address the cellular mechanism of PI3K activation by simvastatin through the use of adenoviral constructs that over-express mutated PI3K isoforms. The role of PI3K in Ca2+ mobilization, activation or inactivation of downstream pathways, and cholesterol-sensitive gene transcription in response to simvastatin will be evaluated. Findings from this work will contribute to the understanding of simvastatin-induced, non lipid-lowering PI3K mediated pathways in human coronary artery endothelium and to significant improvement of current statin treatment.

描述（由申请人提供）：我们的研究重点是蛋白质磷酸肌醇3-激酶（PI3K）家族，以维持心血管健康和心血管疾病的进展。这项研究建议的目的是更好地理解细胞内信号传导机制和3-羟基-3-甲基甲基甲基（HMG）辅酶A（COA）还原酶抑制剂（汀类药物）介导的PI3K介导的3-羟基-3-甲基甲基甲基（HMG）辅酶A（COA）辅酶的后果。特定的PI3K同工型介导不同的功能。例如，在心脏中，PI3K可以刺激病理和生理反应，而这种明显差异的关键似乎是基于激活PI3K同工型的。该提案中的具体目的将检验以下假设：刺激PI3K同工型或同工型的子集会导致响应于辛伐他汀的响应于辛伐他汀，这与脂质降低无关。该方法将通过使用过表达突变的PI3K同工型来解决辛伐他汀通过辛伐他汀通过辛伐他汀激活的细胞机制。 PI3K在CA2+动员，下游途径的激活或灭活中的作用以及胆固醇敏感的基因转录对辛伐他汀的响应。这项工作的发现将有助于理解辛伐他汀诱导的，非脂质的降低PI3K PI3K介导的途径，并在人冠状动脉内皮中介导，并显着改善当前他汀类药物的治疗。