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

CCR6 作为表皮 γ δ T 细胞在伤口修复中功能的调节开关

• 批准号: 10291695
• 负责人: JULIE M JAMESON
• 金额: $ 44.7万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291695
• 关键词: Affect; Antigens; Biotechnology; CCL20 gene; CCR6 gene; CXCL1 gene; CXCL10 gene; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Complex; Cytokine Receptors; Data; Defect; Development; Diabetes Mellitus; Educational Background; Epidermis; Flow Cytometry; Functional disorder; Goals; Growth Factor; Histology; Homeostasis; Human; Hyaluronan; Hyperglycemia; Immune system; Infection prevention; Inflammation; Inflammatory; Ligands; Location; Mediating; Mediator of activation protein; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Pathology; Pathway interactions; Patients; Play; Population; Positioning Attribute; Process; Production; Public Health; Regulatory Pathway; Research; Research Project Grants; Rest; Role; Signal Transduction; Site; Skin; Stress; T cell regulation; T-Lymphocyte; TCR Activation; TNF gene; Techniques; Testing; Therapeutic; Thinness; Tissues; Type 2 diabetic; aging population; chemokine; chemokine receptor; cytokine; diabetic; diabetic wound healing; functional outcomes; functional restoration; hands on research; improved; in vivo; keratinocyte; mouse model; new therapeutic target; non-diabetic; non-healing wounds; novel; receptor; repair function; repaired; transcriptomics; undergraduate research experience; undergraduate student; wound; wound closure; wound healing; γδ T cells

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.

项目摘要 慢性非治疗伤口是公共卫生问题，估计影响美国人口的1-2％。到 提高伤口愈合效率并避免负面结果，对 研究伤口修复所需的正常细胞和分子机制。表皮t细胞播放 在小鼠和人类的伤口修复的炎症和增殖阶段中的关键作用。期间 稳态和TCR参与发作时T细胞需要通过趋化因子/ 细胞因子在伤口修复过程中调节功能结果。角质形成细胞上调趋化因子，例如 伤口愈合过程中的CCL20。 CCR6是CCL20的接收器，由T细胞浸润表皮表达， 但是，对其他CCR6功能以及CCR6在表皮T细胞功能中的作用知之甚少。慢性的 2型糖尿病和肥胖症中的细胞因子/趋化因子产生改变表皮T细胞伤口愈合 功能，但是趋化因子在这种改变的功能中的机制和作用尚不清楚。我们在这里 阐明炎症趋化因子（例如CCL20/CCR6）调节的机制的提议 表皮T细胞功能在伤口修复中以及2型糖尿病和肥胖症中的功能障碍。 提出了以下具体目标： AIM 1：确定表皮T细胞CCR6表达如何通过伤口修复调节 非糖尿病瘦肉与糖尿病肥胖小鼠。 AIM 2：阐明CCL20/CCR6在刺激表皮细胞中调节开关中的作用 伤口修复的功能。 AIM 3：确定慢性CCL20暴露如何调节伤口修复中的表皮细胞和 热CCL20是否会阻断糖尿病肥胖小鼠的功能。 这些特定目标将在结合细胞生物学，组织学和体内技术的鼠模型中进行测试。 这项研究很重要，因为识别负责正常表皮细胞的机制 伤口修复中的功能可能定义用于治疗的新目标。此外，本文提出的研究将 描述表皮T细胞功能的糖尿病和肥胖培养基缺陷中的炎症趋化因子如何 在组织内稳态和修复中。需要仔细描述这些机制才能充分理解 表皮如何调节表皮细胞以改善伤口闭合。本文所述的项目将提供 CSUSM本科生的动手研究机会。参加该研究项目 将影响他们竞争性地申请研究生水平教育或生物技术职位的能力。一起 该实验计划将随着表皮T细胞的新机制的发展而达到顶点 可以评估以改善肥胖症伤口修复并提供独特的研究机会的法规 对于本科生。