Effects of HMG-coA Reductase Pathway Inhibitors on GCAD

HMG-coA 还原酶途径抑制剂对 GCAD 的影响

• 批准号: 7158362
• 负责人: WILLIAM STEIN
• 金额: $ 5.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2008-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158362
• 关键词: G protein; HMG coA reductases; alkyltransferase; atorvastatin; bioluminescence; cardiovascular disorder prevention; chemoprevention; coronary disorder; geranyl compound; green fluorescent proteins; heart transplantation; immunopharmacology; laboratory mouse; microarray technology; morphometry; oxidoreductase inhibitor; postdoctoral investigator; squalene; transplant rejection

DESCRIPTION (provided by applicant): Chronic rejection is the leading cause of death in heart transplant patients, yet, no effective treatment exists. One therapy that has shown promise is the use of HMG-CoA reductase inhibitors (statins), but the mechanism by which they operate remains unclear. This proposal describes a research project designed to delineate the role of HMG-CoA reductase pathway inhibitors in the prevention of chronic rejection in a murine cardiac transplant model. In addition, this project will lead to a greater understanding of the pathways affected in the formation of chronic rejection. This will be done by employing a novel model of chronic rejection which relies on bioluminescence imaging. The project has four specific aims: (1) the development and validation of the FVB Luciferase-GFP (beta-actin) to C57BL/6 cardiac transplant model of chronic rejection; (2) determination of the ability of atorvastatin to decrease the degree of chronic rejection in the model; (3) analysis of the ability of specific HMG-CoA reductase pathway inhibitors to suppress chronic rejection in this model; and (4) examination of the intracellular pathways affected by inhibition of the HMG- CoA reductase pathway using gene microarrays.

描述（申请人提供）：慢性排斥反应是心脏移植患者死亡的主要原因，但尚无有效的治疗方法。一种已显示出前景的疗法是使用 HMG-CoA 还原酶抑制剂（他汀类药物），但其作用机制仍不清楚。该提案描述了一个研究项目，旨在描述 HMG-CoA 还原酶途径抑制剂在预防小鼠心脏移植模型中慢性排斥反应中的作用。此外，该项目将有助于更好地了解慢性排斥反应形成过程中受影响的途径。这将通过采用依赖于生物发光成像的新型慢性排斥模型来完成。该项目有四个具体目标：（1）开发和验证FVB Luciferase-GFP（β-actin）到C57BL/6慢性排斥反应心脏移植模型； (2)测定阿托伐他汀降低模型慢性排斥反应程度的能力； (3)分析特定HMG-CoA还原酶途径抑制剂抑制该模型中慢性排斥反应的能力； (4)使用基因微阵列检查受HMG-CoA还原酶途径抑制影响的细胞内途径。