The Immune Response to Viral Vector and Transgenes in the Fetus

描述（申请人提供）：我的长期职业目标是获得一个学术职位，可以进行基因治疗和免疫学方面的研究，并继续在移植方面的实践。我的短期目标是在免疫学方面获得新的技能和知识。我申请K08是为了继续我在基因治疗方面的训练，并获得免疫学方面的专业知识。我在基因治疗研究方面的经验为我的这一追求提供了坚实的基础，我相信在免疫学、耐受性和T调节细胞方面的专家Jerzy Kupiec-Weglinski博士的指导下进行的额外培训将使我对免疫学有一个基本的了解，这将帮助我发展成为一个富有成效的独立研究者。我的职业发展计划包括实验室工作、辅导以及遗传学和免疫学课程。我的临床和教学职责将受到限制。我与加州大学洛杉矶分校免疫学和基因治疗社区的互动，以及我的顾问委员会，将大大增加我的训练，并为我提供重要的榜样。这些相互作用为成为一名独立的科学家提供了理想的环境。我的总体目标是研究转基因编码蛋白进入发育中的免疫系统后的免疫反应。在免疫成熟之前基因的表达可以诱导耐受。耐受性或免疫功能紊乱可能对分泌蛋白紊乱的治疗产生影响。我提出了一种基于卵白蛋白的子宫内基因转移模型，以定义在aav介导的基因表达后导致抗原特异性无反应的事件。我将研究子宫内注射小鼠耐受诱导和抑制/免疫偏差的机制，并与成年动物的T细胞启动和中和反应进行比较。综上所述，这些研究将提供aav介导的子宫内基因转移后转基因产物特异性T细胞反应的分析。

DESCRIPTION (provided by applicant): My long-term career goal is to have an academic position that allows me to conduct research in gene therapy & immunology and continue a practice in transplantation. My short-term goal is to acquire new skills and knowledge in immunology. I am applying for a K08 in order to continue my training in gene therapy and to obtain expertise in immunology. My experience in gene therapy research has provided me with a solid foundation for this pursuit, and I believe that additional training under the guidance of Dr. Jerzy Kupiec-Weglinski, an expert in immunology, tolerance & T regulatory cells, will allow me to develop a fundamental understanding of immunology that will help me to develop into a productive independent investigator. My career development plan includes laboratory work, mentoring, and courses in genetics & immunology. My clinical & teaching duties will be limited. My interactions with the UCLA immunology and gene therapy community, along with my advisory committee, will add significantly to my training and provide me with important role models. These interactions provide an ideal environment to mature into an independent scientist. My overall goal is to examine the immune response to transgene-encoded proteins when delivered to the developing immune system. Expression of genes prior to the maturation of immunity may enable induction of tolerance. Tolerance or immunological anergy could have an impact on the treatment of disorders of secretory proteins. I am proposing an in utero gene transfer model based on the protein ovalbumin to define the events leading to antigen-specific unresponsiveness after AAV-mediated gene expression. I will investigate mechanisms of tolerance induction and suppression/immune deviation in in utero-injected mice compared to the T cell priming and neutralizing responses in adult animals. Taken together, these studies will provide an analysis of transgene product-specific T cell responses following AAV-mediated gene transfer in utero. This research proposal is designed to elucidate a unique feature of the fetal immune system: the development of tolerance. Understanding how tolerance to proteins occurs is important in the treatment of many diseases. These studies will utilize a gene therapy vector in a fetal mouse model to determine if tolerance can be induced to 'non-self proteins important in therapy.