The overall goal of this proposal is to provide the principal investigator (PI) with the experiences and skills necessary to become an independent researcher, with the focus on studying immune cell trafficking mechanisms. My long-term career goal is to establish a comprehensive and independent research program dedicated to dissect the trafficking mechanism of immune cells in inflammatory and infectious corneal disease, leading to new therapeutic targets. Corneal antigen-presenting cells (APC) have a critical role in maintaining the clarity of the cornea and preserving vision. APC-mediated immune responses require contact-dependent information exchange between APC and T cells. Ag presentation by mature DC to naive T cells induces T cell activation and proliferation into effector T cells, which is in turn thought to be controlled by several mechanisms, including the action of regulatory T cells (Treg). Career decisions taken by APC are regulated molecules on the surface of APC and T cells. Despite their unique position in the immune system, the signals APC need to enter the cornea, and the clues they require to leave the cornea, are still largely unexplored. In preliminary work for this project, we have developed a new multiphoton intravital microscopy (MP-IVM) model to study APC in intact corneas of anesthetized mice. This imaging approach uses transgenic mice, in which APC subsets expresses distinct genetically encoded fluorescent tags, and produces 3D time-lapse movies of APC at subcellular resolution, interacting with surrounding cells. These cells will be studied to investigate the traffic signals that guide them to normal and inflamed corneas and will be used to address the following three specific aims: 1.) To dissect the molecular mechanisms by which APC travel to normal and inflamed corneas;2.) To analyze the mechanisms involved in migration of APC from the cornea to local lymph nodes under normal conditions and during inflammation;and 3) examine the spatial, temporal and behavioral characteristics of donor and host APC after corneal transplantation and their interaction with T cells in lymph nodes.
This aim will also analyze how effector T cells or Tregs enter the cornea. The proposed experiments will generate a comprehensive, mechanism-oriented survey of the behavioral similarities and differences between distinct APC subsets under normal condition and inflammation.
Identification of critical pathways of immune cell migration to and from the cornea from the proposed studies, will provide new molecular targets for pharmacological intervention in inflammatory, infectious, and autoimmune corneal diseases, as well as in corneal transplantation. These targets may lead to novel and highly specific strategies for immunotherapy, through modulation of immune cell trafficking.
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