Project Summary Chronic nonhealing wounds are a public health concern affecting an estimated 1-2% of the U.S. population. To increase wound healing efficiency and avoid negative outcomes, it is becoming increasingly important to investigate the normal cellular and molecular mechanisms required for wound repair. Epidermal T cells play key roles in the inflammation and proliferation stages of wound repair in mice and humans. During homeostasis and upon TCR engagement epidermal T cells require additional signals via chemokine/ cytokines to regulate functional outcomes during wound repair. Keratinocytes upregulate chemokines such as CCL20 during wound healing. CCR6, the receptor for CCL20, is expressed by T cells infiltrating the epidermis, but less is known about other CCR6 functions and the role of CCR6 in epidermal T cell function. Chronic cytokine/chemokine production in type 2 diabetes and obesity alters epidermal T cell wound healing functions, but the mechanism and role of chemokines in this altered function is not well understood. Here we propose to elucidate the mechanisms by which inflammatory chemokines such as CCL20/CCR6 regulate epidermal T cell function in wound repair and how dysfunction occurs in type 2 diabetes and obesity. The following specific aims are proposed: Aim 1: Determine how epidermal T cell CCR6 expression is modulated by wound repair in nondiabetic lean versus diabetic obese mice. Aim 2: Elucidate the role of CCL20/CCR6 in stimulating a regulatory switch in epidermal T cell function in wound repair. Aim 3: Identify how chronic CCL20 exposure modulates epidermal T cells in wound repair and whether therapeutic CCL20 blockade restores function in diabetic obese mice. These specific aims will be tested in murine models combining cell biology, histology, and in vivo techniques. This research is significant because identifying the mechanisms responsible for normal epidermal T cell function in wound repair may define new targets for therapeutics. In addition, the studies proposed herein will delineate how inflammatory chemokines in diabetes and obesity mediate defects in epidermal T cell function in tissue homeostasis and repair. Carefully delineating these mechanisms is required for a full understanding of how epidermal T cells are regulated to improve wound closure. The projects described herein will provide hands-on research opportunities for undergraduate students at CSUSM. Participating in this research project will impact their ability to competitively apply for graduate level education or biotechnology positions. Together this experimental plan will culminate with the development of novel mechanisms of epidermal T cell regulation that can be evaluated to improve wound repair in obesity and provide unique research opportunities for undergraduate students.