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: 7346990
• 负责人: WILLIAM STEIN
• 金额: $ 4.19万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7346990
• 关键词: Actins; Acute; Affect; Animal Model; Animals; Apoptosis; Area; Biology; Bioluminescence; C57BL/6 Mouse; Cardiac; Cause of Death; Cholesterol; Chronic; Coenzyme A; Coronary Arteriosclerosis; Daily; Data; Databases; Development; Disruption; Fellowship; Functional disorder; Future; GTP-Binding Proteins; Genes; Goals; Graft Rejection; Green Fluorescent Proteins; Heart; Heart Transplantation; Hydroxymethylglutaryl-CoA reductase; Image; Imaging Techniques; Immunosuppression; Individual; Injection of therapeutic agent; Lead; Luciferases; Modeling; Molecular; Monitor; Mus; Myocardium; Names; Oxidoreductase; Pathway interactions; Play; Postoperative Period; Prevention; Proteins; Receptor Signaling; Regulation; Research Project Grants; Role; Squalene Synthetase; Survival Rate; System; Testing; Therapeutic immunosuppression; Transferase; Transplant Recipients; Transplantation; Validation; Work; animal data; atorvastatin; beta Actin; cytokine; design; inhibitor/antagonist; insight; novel; prevent; protein farnesyltransferase; research study; therapeutic target

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（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。