I am seeking a K01 Mentored Research Scientist Award to obtain additional training to build a foundation from which to successfully make a transition to become an independent investigator in immunology. My long-term research goal is to define signal transduction pathways that coordinate T cell migration and activation during immune responses under physiological and pathological conditions. I intend to pursue this goal in an independent, tenure-track position at UCSF or a comparable academic institution, with the goal of becoming a leader in this field. I studied the signal transduction pathways that regulate the activation of B cells under the mentorship of Dr. K. Mark Coggeshall as a graduate student at the Ohio State University. My research resulted in eight publications in highly respected scientific journals. I joined the laboratory of Dr. Arthur Weiss at UCSF as a postdoctoralscholar with the aim of investigating one of the signal transduction pathways that is critical for T cell activation. During my postdoctoral years, my efforts focused on understanding the functions and activation mechanisms of the trimolecular complex of GIT2, PIX and PAK that plays a crucial role in regulating T cell migration and activation. I have found that the PIX-dependent pathway plays an important role in recruiting and activating PAK. These results were published in and featured on the cover of Nature Immunology in 2005. Recently, I demonstrated that GIT2 suppress chemokine-mediated thymocyte migration via a mechanism involving inhibition of Rac activation and regulates positive selection. We are currently revising a paper that received very positive reviews for publication in Nature Immunology. In recognition of my research, I was awarded the Career Development Special Fellow Award by the Leukemia and Lymphoma Society, which supported me for the last three years. Furthermore, I became an assistant adjunct professor in the Division of Rheumatology at UCSF. My extensive research experience in the field of T cell activation and migration puts me in a strong position to explore how the cellular machinery that incorporates cytoskeletal and signaling networks coordinates immune responses. Although I have created my own research niche and generated valuable mouse models since I joined the Weiss laboratory, I realized that additional training in the field of two-photon microscopy and arthritis pathogenesis will significantly expand my research in determining important players that orchestrate cytoskeletal regulation and T cell activation during immune responses under normal and pathological conditions. The K01 award would allow me to obtain the additional training in two-photon microscopy and generate crucial animal reagents required for an R01 application, and will facilitate my transition to a completely independent investigator. The research environment in which I will be training is outstanding. UCSF has an excellent and well- established reputation in biomedical research, and it is considered one of the nation's top-ranked health sciences, training, and research centers. The Department of Microbiology and Immunology and the Division of Rheumatology at UCSF host a collection of highly distinguished faculty members in immunology and in signal transduction who have diverse interests and disciplines in multiple problems in immunology and immunological diseases. I will fully take advantage of rich scientific environment to receive training and inputs. Research: I have pioneered research on the roles and mechanisms of activation of PAK and its binding partners, PIX and GIT2, in T cells, but much remains to be investigated. Previously, I demonstrated that PAK, PIX and GIT are recruited to the T cell immunological synapse and this recruitment is critical for T cell activation. Recently, I found that loss of GIT2 enhances the migration responses of pre-selecting DP thymocytes to SDF-1 or CCL25 and increases Rac activation and actin polymerization. Moreover, loss of GIT2 impairs positive selection in vivo, suggesting that aberrations in cytoskeletal reorganization in GIT2-/- thymocytes may interfere with efficient positive selection in the thymus. Based on these findings, I hypothesize (1) that GIT2 regulates cytoskeletal processes that govern chemokine-mediated migration of T cells;(2) PAK and PIX play a critical role in signaling events following TCR stimulation that lead to T cell activation and cytoskeletal reorganization;and (3) regulation of cytoskeletal reorganization and T cell activation by GIT2 and PAK2 contributes to the development and perpetuation of arthritis. To determine the role of the GIT2-PIX-PAK complex in immune cell migration and activation in physiological and arthritic settings, I propose three specific aims. First, I will determine the role of GIT2 in T cell migration and cytoskeletal reorganization using GIT2-/- mice. Second, I will define the function of PAK2 and PIX in T cell activation and cytoskeletal reorganization using PAK2 conditional KO mice. Third, I will elucidate the roles of GIT2 and PAK2 in Th1, Th2 and Th17 effector T cell function and migration and in the development of arthritis. These approaches will clarify the importance of the GIT2-PIX-PAK complex in normal T cell migration and activation and may provide insights into mechanisms relevant to T cell autoimmunity that could lead to novel therapeutics.
The study of signal transduction pathways that control T cell migration and activation is critical for understanding the mechanisms of T cell development, activation and effector function and the pathology of autoimmune inflammatory diseases. Many autoimmune diseases, including rheumatoid arthritis, have shown aberrations in cell migration and activation;thus, understanding the basic mechanisms governing these processes may help in the development of new therapies to treat these diseases.