GENETIC TREATMENT FOR ATHEROSCLEROSIS

本研究的目的是确定动脉粥样硬化易感性的靶基因，并开发用于治疗高脂血症的人类基因疗法。研究将通过建立血脂异常小鼠模型来确定导致动脉粥样硬化的遗传因素。我们将使用这些模型来阐明疾病的分子机制并评估新的治疗方法。该建议旨在建立使用腺相关病毒载体在患病动物核酶基因传递的有效性。研究还将通过产生表达核酶的转基因小鼠来研究将核酶作为潜在治疗剂的功效。研究还将通过在体内使用辅助依赖腺病毒载体来探讨多基因一起传递的新方法，以评估该策略对高脂血症治疗的协同作用。综上所述，这些研究将提供对动脉粥样硬化易感性的潜在靶点的理解。该研究将对apoB mRNA锤头核酶的结构/功能的理解以及将该核酶作为治疗动脉粥样硬化的药物的可能应用提供新的见解。

The objective of this proposed research is to define target gene(s) underlying predisposition to atherosclerosis and to develop human gene therapy for the treatment of hyperlipidemia. Studies will be carried out to define genetic factor(s) that contributes to atherosclerosis by developing dyslipidemia murine model. We will use these models to elucidate the molecular mechanisms of the disease and to evaluate novel therapeutics. The proposal seeks out to establish the effectiveness of using adeno-associated virus vector for gene delivery of ribozyme in diseased animals. Studies will also investigate the efficacy of using ribozyme as a potential therapeutic agent by generating transgenic mouse expressing ribozyme. Studies will also address new approaches for gene delivery of multiple genes together by using helper-dependent adenovirus vector in vivo to evaluate the synergistic effect of this strategy on the treatment for hyperlipidemia. Taken together, these studies will provide understanding of target(s) underlying predisposition to atherogenesis. The study will shed new insights to the understanding of the structure/function of the apoB mRNA hammerhead ribozyme, and the possible application of using this ribozyme as a therapeutic agent for the treatment of atherosclerosis.