Effects of HMG-coA Reductase Pathway Inhibitors on GCAD

描述（由申请人提供）：慢性排斥反应是心脏移植患者死亡的主要原因，但目前还没有有效的治疗方法。一种有希望的治疗方法是使用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慢性排斥反应中的作用。此外，该项目将导致对慢性排斥形成的影响途径的更好理解。这将通过采用依赖于生物发光成像的慢性排斥反应的新模型来完成。本项目有四个具体目标：（1）开发和验证FVB荧光素酶-GFP（2）测定阿托伐他汀降低该模型中慢性排斥程度的能力;（3）分析特异性HMG-CoA还原酶途径抑制剂抑制该模型中慢性排斥的能力;和（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。

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.