CCR6 as a Regulatory Switch for Epidermal gamma delta T Cell Function in Wound Repair

项目摘要 慢性无法愈合的伤口是一个公共卫生问题，估计有1%-2%的美国人口受到影响。至 提高伤口愈合效率并避免负面后果，越来越重要的是 研究创伤修复所需的正常细胞和分子机制。表皮T细胞的作用 在小鼠和人类伤口修复的炎症和增殖阶段发挥关键作用。在.期间 动态平衡和TCR结合时，表皮T细胞需要通过趋化因子/ 在伤口修复过程中调节功能结果的细胞因子。角质形成细胞上调趋化因子，如 CCL20在伤口愈合过程中的作用。CCL20的受体CCR6是由渗入表皮的T细胞表达的， 但对CCR6的其他功能以及CCR6在表皮T细胞功能中的作用知之甚少。慢性 2型糖尿病和肥胖患者细胞因子/趋化因子的产生改变表皮T细胞伤口愈合 功能，但趋化因子在这种改变的功能中的机制和作用尚不清楚。在这里我们 建议阐明CCL20/CCR6等炎性趋化因子的调节机制 表皮T细胞在伤口修复中的功能以及在2型糖尿病和肥胖症中如何发生功能障碍。 提出了以下具体目标： 目的1：研究创伤修复对小鼠皮肤T细胞CCR6表达的影响 非糖尿病瘦小鼠与糖尿病肥胖小鼠。 目的2：阐明CCL20/CCR6在刺激表皮T细胞调节开关中的作用 在伤口修复中的作用。 目的3：确定慢性接触CCL20如何调节创面修复和修复过程中的表皮T细胞 治疗性CCL20阻断能否恢复糖尿病肥胖小鼠的功能。 这些特定的目标将在结合细胞生物学、组织学和活体技术的小鼠模型中进行测试。 这项研究具有重要意义，因为它确定了导致正常表皮T细胞的机制 在伤口修复中的作用可能为治疗学定义新的靶点。此外，本文提出的研究将 糖尿病和肥胖症患者炎性趋化因子如何介导表皮T细胞功能缺陷 在组织动态平衡和修复方面。需要仔细描述这些机制，才能充分理解 表皮T细胞如何调节以改善伤口闭合。这里描述的项目将提供 为南加州理工大学本科生提供实践研究机会。参与这项研究项目 会影响他们竞争申请研究生教育或生物技术职位的能力。同舟共济 这项实验计划将随着表皮T细胞新机制的发展而达到顶峰 可评估为改善肥胖患者伤口修复并提供独特研究机会的调节 对本科生来说。

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.