Mechanism-Based Wound Healing by Activation of gamma delta T Cells

通过激活 γ δ T 细胞实现基于机制的伤口愈合

• 批准号: 8954537
• 负责人: Wendy L. Havran
• 金额: $ 22.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8954537
• 关键词: Acceleration; Affect; Amputation; Binding; Blood; CAR receptor; Cell Surface Receptors; Cells; Chemistry; Chronic; Clinical; Complex; Country; Data; Decubitus ulcer; Defect; Dendrites; Development; Disabled Persons; Disease; Elderly; Environment; Epidermis; Epithelial; Epithelial Cells; Exposure to; Foot Ulcer; Future; Gel; Growth Factor; Healed; Health Care Costs; Healthcare; Human; Hydrogels; Immune system; Immunologic Surveillance; Impaired wound healing; Inflammatory; Injury; Intestines; Lead; Ligands; Lung; Lymphoid Tissue; Malignant Neoplasms; Mediating; Minor; Molecular; Monitor; Morbidity - disease rate; Mus; Nature; Patients; Personal Satisfaction; Phase; Play; Population; Process; Production; Proteins; Refractory; Reporting; Risk; Role; Signal Transduction; Site; Skin; T cell anergy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Topical application; Trauma; Wound Healing; anergy; base; cell injury; chemokine; combat; cytokine; design; diabetic; diabetic patient; healing; improved; in vivo; junctional adhesion molecule; keratinocyte; killings; mortality; nanoparticle; novel therapeutics; older patient; pathogen; public health relevance; receptor binding; receptor expression; tissue repair; tumor; wound

 DESCRIPTION (provided by applicant): Epithelial barrier tissues, including the skin, provide an interface between the body and the environment. The constant exposure to injury in the skin requires efficient tissue repair processes. gd T cells preferentially reside in epithelial tissues where they perform immune surveillance functions and can rapidly respond to tissue injury. Epidermal gd T cells contribute to wound healing through production of growth factors, cytokines and chemokines that regulate the inflammatory and reepithelialization phases of wound repair. Costimulatory signals are required for effective gd T cell activation and participation in wound healing and are delivered by junctional adhesion molecule-like protein (JAML) on gd T cells binding to its ligand Coxsackie and Adenovirus receptor (CAR) expressed by wounded keratinocytes. Epidermal gd T cells are anergic and unable to contribute wound healing functions in patients with chronic wounds. JAML-CAR interactions are dysregulated in these patients suggesting that lack of costimulatory signals for gd T cells may be responsible for the impaired healing. We hypothesize that providing costimulatory signals to gd T cells through sustained delivery of JAML ligands to wounds will accelerate healing of chronic wounds. We will test this hypothesis by developing degradable hydrogels for topical delivery of JAML- or CAR-binding ligands to chronic wounds and then evaluating the effects of these gels on mechanisms of gd T cell-mediated wound healing. The elderly, disabled, diabetic and other patients are at risk for development of chronic wounds that not only affect patient morbidity and mortality but are also an increasing healthcare burden. If delivery of costimulatory ligands improves healing, the strategies developed here will be the basis of future approaches for acceleration of healing of human chronic wounds.

 描述（由申请方提供）：上皮屏障组织（包括皮肤）在身体和环境之间提供界面。持续暴露于皮肤损伤需要有效的组织修复过程。gd T细胞优先驻留在上皮组织中，在那里它们执行免疫监视功能并且可以快速响应组织损伤。表皮gd T细胞通过产生调节伤口修复的炎症和上皮再形成阶段的生长因子、细胞因子和趋化因子而有助于伤口愈合。共刺激信号是有效的gd T细胞活化和参与伤口愈合所必需的，并且通过gd T细胞上的连接粘附分子样蛋白（JAML）与其配体科萨基和由受伤的角质形成细胞表达的腺病毒受体（CAR）结合来递送。表皮gd T细胞无反应性，无法对慢性伤口患者的伤口愈合功能做出贡献。在这些患者中，JAML-CAR相互作用失调，表明缺乏gd T细胞的共刺激信号可能是导致愈合受损的原因。我们假设通过持续向伤口递送JAML配体向gd T细胞提供共刺激信号将加速慢性伤口的愈合。我们将通过开发可降解水凝胶来测试这一假设，该水凝胶用于将JAML或CAR结合配体局部递送至慢性伤口，然后评估这些凝胶对gd T细胞介导的伤口愈合机制的影响。老年人、残疾人、糖尿病患者和其他患者有发生慢性伤口的风险，这不仅影响患者的发病率和死亡率，而且还增加了医疗保健负担。如果共刺激配体的递送改善愈合，那么这里开发的策略将是未来加速人类慢性伤口愈合的方法的基础。