This proposal describes a 5-year training program for the development of an academic career in the field of cutaneous immunology. Through the proposed training program, the candidate will expand upon her scientific skills and become an independent investigator studying immunological responses in the skin. The career development will be enhanced by coursework, participation in seminars and conferences, national and international presentations, and engagement in her mentored research project. To enhance the candidate's training, her mentor and an advisory committee will provide excellent scientific and career advice. The central hypothesis tested by this proposal is that extracellular ATP signaling is crucial for host surveillance function by human skin-resident T cells to protect from UV damage. This hypothesis will be tested by the following experiments: 1) determining the functional role of eATP signaling on expression of cytokines and effector molecules by skin-resident T cells and their capacity to induce repair and defense genes or apoptosis in keratinocytes;2) examining whether CD39+ cells impair skin-resident T cell function and 3) elucidating the efficacy of purinergic receptor directed strategies to prevent and treat UV-induced skin inflammation and pre- cancer lesions. The proposed studies will expand our knowledge of how ATP regulates surveillance functions in skin-resident T cells, evaluate new in vitro and in vivo models of skin inflammation, identify candidate purinergic receptors for drug targeting, and develop new tools for investigating and treating UV-induced skin inflammation and actinic keratoses to prevent tissue damage and malignant transformation. The research and career development components of this K08 award provide the ideal setting for the applicant to become a successful independent investigator and to establish an independent research program.
This project investigates the functional roles of skin-resident T cells in UV-induced skin inflammation, skin cancer and precursor lesions, and focuses on the development of new models and treatments. Release of an endogenous stress signal is shown to regulate cutaneous T cell responses aimed at keratinocyte repair and protection of UV damage.
|Lai, Chester; August, Suzannah; Albibas, Amel et al. (2016) OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential. Clin Cancer Res 22:4236-48|
|Chen, Yong; Fang, Quan; Wang, Zilong et al. (2016) Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. J Biol Chem 291:10252-62|
|MacLeod, Amanda S; Rudolph, Ross; Corriden, Ross et al. (2014) Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. J Immunol 192:5695-702|
|Grover, Rajesh K; Zhu, Xueyong; Nieusma, Travis et al. (2014) A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union. Science 343:656-61|