NOVEL METHODS OF GENE THERAPY FOR LIVER DISEASE

描述(取自应用程序) 这位候选人目前是医学临床讲师，也是 加州大学旧金山分校分子医学培训计划。他的长期职业目标是 成为一名富有成效的独立研究的生物医学研究员 专注于开发新的和临床适用的基因的计划 肝脏基因治疗的递送系统。为了实现这一目标，候选人 与他的研究导师Y.W.Kan博士一起开发了一种结构化的 职业发展计划，结合了一项监督研究 课程以及研究生课程工作和专业讲习班。这个 候选人的研究提案探索了肝脏基因的两种新策略 传递，一种基于逆转录病毒载体，另一种基于腺病毒 向量。高效、有选择地提供治疗的能力 在体内将基因转移到肝细胞将代表着在 遗传性和获得性肝脏疾病的治疗。 不幸的是，目前可用的递送系统中没有一个会导致 这是肝脏特有的表达，有效和持久。基因 通过逆转录病毒载体传递，最常用的策略是 临床试验，结果是基因的稳定整合，从而允许 持久表达，但当前一代逆转录病毒载体是 既没有针对性，也没有效率。应聘者计划设计、工程、 并测试既有效又针对肝细胞的逆转录病毒载体 作为研究计划的一部分。他的假设是建立在概念上的 在导师的实验室里做了大量的工作，这是具体的吗 可以实现逆转录病毒载体的靶向和提高效率 通过有目的地操纵配体-受体的相互作用。在……里面 为了验证这一假设，候选人计划将组织重定向 逆转录病毒载体包膜蛋白工程的趋向性研究 与肝细胞上的受体特异结合的配体。在研究中 作为补充，候选人还将测试是否专注于 使用他拥有的重组融合蛋白CTLA4Ig进行免疫调节 设计和建造将专门颠覆破坏性免疫 阻碍腺病毒基因传递的反应。这些研究是在 一个出色的研究环境，作为结构化职业生涯的一部分 开发计划，将提供技术研究技能、理论 以及候选人在开始职业生涯时需要的概念化 一名独立调查员。

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.