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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Study Section
Allergy & Clinical Immunology-1 (AITC)
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Vitkovic, Ljubisa
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Tai, Denise S; Hu, Chuhong; Kim, Elizabeth H et al. (2015) Augmentation of transgene-encoded protein after neonatal injection of adeno-associated virus improves hepatic copy number without immune responses. Pediatr Res 78:239-246
Tai, D S; Hu, C; Lee, C C I et al. (2015) Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies. Gene Ther 22:923-30
Hu, Chuhong; Kasten, Jennifer; Park, Hana et al. (2014) Myocyte-mediated arginase expression controls hyperargininemia but not hyperammonemia in arginase-deficient mice. Mol Ther 22:1792-802
Awe, Jason P; Lee, Patrick C; Ramathal, Cyril et al. (2013) Generation and characterization of transgene-free human induced pluripotent stem cells and conversion to putative clinical-grade status. Stem Cell Res Ther 4:87
Kasten, Jennifer; Hu, Chuhong; Bhargava, Ragini et al. (2013) Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. Mol Genet Metab 110:222-30
Lee, E K; Hu, C; Bhargava, R et al. (2013) AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. Gene Ther 20:785-96
Hu, C; Lipshutz, G S (2012) AAV-based neonatal gene therapy for hemophilia A: long-term correction and avoidance of immune responses in mice. Gene Ther 19:1166-76
Lee, Eun K; Hu, Chuhong; Bhargava, Ragini et al. (2012) Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy. Mol Ther 20:1844-51
Hu, Chuhong; Cela, Racel G; Suzuki, Masataka et al. (2011) Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII. Proc Natl Acad Sci U S A 108:2082-7
Schnickel, Gabriel T; Busuttil, Ronald W; Lipshutz, Gerald S (2011) Improvement in short-term pancreas transplant outcome by targeted antimicrobial therapy and refined donor selection. Am Surg 77:1407-11

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