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.
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