GENETIC TREATMENT FOR ATHEROSCLEROSIS

本研究的目的是明确动脉粥样硬化易感性的靶基因(S)，并开发治疗高脂血症的人类基因疗法。将通过建立血脂异常的小鼠模型来确定导致动脉粥样硬化的遗传因素(S)。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。该提案旨在确定使用腺相关病毒载体在患病动物体内进行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用作潜在治疗剂的效果。研究还将探讨通过体内辅助依赖腺病毒载体将多个基因一起进行基因传递的新方法，以评估这一策略在治疗高脂血症方面的协同效应。综上所述，这些研究将提供对靶点(S)潜在的动脉粥样硬化易感性的理解。本研究将为了解apoB基因锤头状核酶的结构和功能，以及利用该核酶作为治疗药物治疗动脉粥样硬化提供新的思路。

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.