The Immune Response to Viral Vector and Transgenes in the Fetus

描述（由申请人提供）：我的长期职业目标是有一个学术地位，使我能够进行基因治疗和免疫学研究，并继续在移植实践。我的短期目标是获得免疫学方面的新技能和知识。我申请K 08是为了继续我在基因治疗方面的培训，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基本的了解，这将有助于我发展成为一名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，指导，以及遗传学和免疫学课程。我的临床和教学职责将是有限的。我与加州大学洛杉矶分校免疫学和基因治疗社区的互动，沿着我的顾问委员会，将大大增加我的培训，并为我提供重要的榜样。这些互动提供了一个理想的环境，成熟为一个独立的科学家。我的总体目标是检查转基因编码的蛋白质传递到发育中的免疫系统时的免疫反应。在免疫成熟之前基因的表达可以诱导耐受。耐受性或免疫无反应性可能对分泌性蛋白质疾病的治疗产生影响。我提出了一个在子宫内的基因转移模型的基础上，蛋白卵清蛋白定义的事件，导致抗原特异性无反应后，AAV介导的基因表达。我将研究子宫注射小鼠中的耐受诱导和抑制/免疫偏离机制，与成年动物中的T细胞引发和中和反应相比。总之，这些研究将提供在子宫内AAV介导的基因转移后转基因产物特异性T细胞应答的分析。 这项研究计划旨在阐明胎儿免疫系统的一个独特特征：耐受性的发展。了解对蛋白质的耐受性如何发生在许多疾病的治疗中是重要的。这些研究将在胎鼠模型中利用基因治疗载体，以确定是否可以诱导对治疗中重要的非自身蛋白质的耐受性。

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.