NOVEL METHODS OF GENE THERAPY FOR LIVER DISEASE

描述（取自应用程序） 候选人目前是医学临床导师和 加州大学旧金山分校分子医学培训项目 他的长期职业目标是 成为一名富有成效的生物医学调查员， 该计划侧重于开发新的和临床适用的基因 用于肝基因治疗的递送系统。 为了实现这一目标，候选人 沿着他的研究导师Y.W.博士简，结构化 职业发展计划，包括监督研究 课程以及研究生课程工作和专门讲习班。 的 候选人的研究计划探索了两种新的肝脏基因策略 递送，一种基于逆转录病毒载体，另一种基于腺病毒载体， 向量。 有效和选择性地递送治疗药物的能力 基因在体内肝细胞中的表达将代表着 治疗遗传性和后天性肝病。 不幸的是，目前可用的输送系统中没有一个导致 表达是肝脏特异性的、有效的和持久的。 基因 通过逆转录病毒载体进行递送，这是治疗中最常用的策略。 临床试验，导致基因的稳定整合，从而允许 持久表达，但当前一代的逆转录病毒载体 既没有针对性，也没有效率。 候选人计划设计，工程师， 并测试既有效又有肝细胞特异性的逆转录病毒载体 作为研究计划的一部分。 他的假设是基于概念上的 在导师的实验室里所做的大量工作， 可以实现逆转录病毒载体的靶向和增强的效率 通过有目的地操纵配体-受体相互作用。 在 为了验证这一假设，候选人计划重新定向组织， 逆转录病毒载体的趋向性，通过将其工程化到它们的包膜蛋白中 特异性结合肝细胞上受体的配体。 研究中 除此之外，候选人还将测试是否专注 免疫调节使用重组融合蛋白，CTLA 4 Ig，他已经 设计和建造的，将专门破坏破坏性免疫 这些反应阻碍了腺病毒基因的传递。 这些研究，在 杰出的研究环境作为结构化职业生涯的一部分 发展计划，将提供技术研究技能，理论， 以及候选人需要开始职业生涯的概念化， 独立调查员

DESCRIPTION (taken from application) The candidate is currently a Clinical Instructor in Medicine and a Fellow in the UCSF Molecular Medicine Training Program. His long-term career goal is to become a productive biomedical investigator with an independent research program focused on the development of novel and clinically-applicable gene delivery systems for hepatic gene therapy. Towards this goal, the candidate has developed, along with his Research Mentor, Dr. Y.W. Kan, a structured career development program that incorporates a supervised research curriculum as well as graduate course work and specialized workshops. The candidate's research proposal explores two novel strategies for hepatic gene delivery, one based on retroviral vectors and the other on adenoviral vectors. The ability to efficiently and selectively deliver therapeutic genes to hepatocytes in vivo would represent a major advance in the treatment of both hereditary and acquired diseases of the liver. Unfortunately, none of the delivery systems currently available results in expression which is liver-specific, efficient and long-lasting. Gene delivery via retroviral vectors, the strategy most commonly employed in clinical trials, results in stable integration of genes, thus permitting long-lasting expression, but the current generation of retroviral vectors is neither targeted nor efficient. The candidate plans to design, engineer, and test retroviral vectors that are both efficient and hepatocyte-specific as part of the research plan. His hypothesis, which is based conceptually on extensive work done in the laboratory of the mentor, is that specific targeting and enhanced efficiency of retroviral vectors can be achieved through the purposeful manipulation of ligand-receptor interactions. In order to test this hypothesis, the candidate plans to redirect the tissue tropism of retroviral vectors by engineering into their envelope proteins ligands that bind specifically to receptors on hepatocytes. In studies complementary to these, the candidate will also test whether focused immunomodulation using a recombinant fusion protein, CTLA4Ig, that he has designed and constructed will specifically subvert the destructive immune responses that thwart adenoviral gene delivery. These studies, performed in an outstanding research environment as part of a structured career development program, will provide the technical research skills, theories and conceptualizations that the candidate will need to launch an career as an independent investigator.