SECOND GENERATION ADENOVIRUS AND VASCULAR GENE TRANSFER

说明：（根据申请改编）基因转移技术是 在基因治疗的激烈评估，但它的真实的承诺可能是作为一个 研究血管生成的分子和细胞机制的工具 疾病 使用腺病毒载体的基因转移已经成功地在 治疗血管球囊损伤后的新生内膜增生，但 载体本身诱导大量炎症和细胞增殖。 幸运的是，第二代腺病毒载体已经大大减少了 病毒复制和结构基因表达，因此， 代表几乎惰性的基因转移载体。 因此，PI将 研究这些新载体对血管基因转移的影响， 确定它们对急性和慢性炎症的作用以及它们的能力 以实现长期的血管转基因表达。 随后，他将 使用此矢量来研究的起源和随后的影响 内皮功能障碍是目前在最早的阶段， 动脉粥样硬化过程中的胆固醇喂养的兔子。 具体来说，他将 确定是否腺病毒转移基因设计，以提高血管 一氧化氮或还原超氧化物将有利地影响动脉粥样硬化 过程 拟议的研究将确定 第二代腺病毒载体改进了第一代载体， 并将确定仍然存在的问题的程度。 此外该 拟议的研究将使用腺病毒基因转移作为一种工具， 了解动脉粥样硬化的早期阶段。 实现 这些目标将有助于我们了解动脉粥样硬化 动脉粥样硬化，并增加血管基因治疗的可能性， 证明是治疗人类动脉粥样硬化的有效选择。

DESCRIPTION: (Adapted from the application) Gene transfer technology is under intense evaluation for gene therapy, but its real promise may be as a tool for investigating the molecular and cellular mechanisms of vascular disease. Gene transfer using adenoviral vectors has been successful in treating neointimal proliferation following vascular balloon injury, but the vector itself induces substantial inflammation and cellular proliferation. Fortunately, second generation adenoviral vectors have substantially reduced viral replication and structural gene expression, and therefore, may represent nearly inert gene transfer vectors. Accordingly, the PI will study the effect of these newer vectors on vascular gene transfer, determining their effect on acute and chronic inflammation and their ability to effect long-term vascular transgene expression. Subsequently, he will use this vector to investigate the origin and subsequent effects of endothelial dysfunction that is present in the earliest phases of the atherogenic process in cholesterol-fed rabbits. Specifically, he will determine whether adenoviral transfer of genes designed to enhance vascular nitric oxide or reduce superoxide will favorably affect the atherosclerotic process. The proposed studies will establish the degree to which second-generation adenoviral vectors improve upon first-generation vectors, and will define the extent of problems that remain. In addition, the proposed studies will use adenoviral gene transfer as a tool to enhance understanding of the early phases of atherosclerosis. The achievement of these goals will contribute to our understanding of atherosclerosis atherogenesis, and increase the likelihood that vascular gene therapy will prove to be an effective option for treatment of human atherosclerosis.