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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR059754-05
Application #
8490314
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mao, Su-Yau
Project Start
2010-07-08
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$119,610
Indirect Cost
$8,860
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611