Altered gamma delta T cell-keratinocyte interplay in the skin of diabetic mice

糖尿病小鼠皮肤中 γ δ T 细胞与角质形成细胞相互作用的改变

• 批准号: 7590800
• 负责人: JULIE M JAMESON
• 金额: $ 41.02万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590800
• 关键词: Address; Affect; Antidiabetic Drugs; Antigens; Apoptosis; Apoptotic; Area; Cell Communication; Cell Count; Cell Survival; Cell physiology; Cells; Chronic; Complex; Complication; Complications of Diabetes Mellitus; Data; Defect; Development; Diabetes Mellitus; Diabetic Foot; Diabetic mouse; Environment; Epidermis; Epithelial; Epithelial Cells; Epithelium; Exhibits; Functional disorder; Funding; Funding Mechanisms; Glucocorticoids; Goals; Grant; Growth Factor; Healed; Homeostasis; Hyperglycemia; IL2RA gene; Immune System Diseases; Immune system; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-2; Intestines; Knowledge; Laboratories; Lead; Lung; Lymphocyte; Mediating; Metformin; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Play; Population; Process; Production; Proliferating; Research; Role; Signal Transduction; Skin; Staging; Stress; Study models; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Ulcer; United States National Institutes of Health; Work; Wound Healing; anergy; base; cytokine therapy; diabetic; experience; healing; improved; in vivo; interest; keratinocyte; mouse model; novel strategies; public health relevance; receptor; receptor expression; repaired; reproductive; response

DESCRIPTION (provided by applicant): Diabetic foot ulcerations are a debilitating complication common to type 1 and 2 diabetes. There is a critical need for studies that identify how diabetes affects cell-cell interactions in epithelial tissues such as the skin, which are very susceptible to damage. Murine skin 34 T cells, also known as dendritic epidermal T cells (DETC), play roles in skin homeostasis and wound repair. The complex cross-talk between the activating keratinocytes and the responding DETC is mediated by receptor expression and growth factor production. Our long-term goal is to determine how diabetes negatively impacts the immune system, with a special focus on epithelial T cell populations. This application will examine how type 2 diabetes alters the survival and function of DETC and whether this can be reversed therapeutically. The working hypothesis is that DETC are chronically stimulated by insulin resistant keratinocytes rendering the DETC apoptotic and eventually anergic. This hypothesis is based on preliminary results, which show that the normal cross-talk between DETC and keratinocytes is altered in diabetic skin. The following specific aims are proposed: (1) determine why DETC are diminished in the skin of mice with type 2 diabetes, (2) identify the contribution of keratinocyte-DETC cross-talk to DETC dysfunction in diabetic mice, and (3) restore DETC numbers and function in diabetic mice. Once we identify how DETC are suppressed in diabetic mouse skin we may be able to restore activation and exploit their wound healing potential. These specific aims will be tested by examining how DETC numbers decline in diabetic skin and whether the remaining DETC are rendered functionally unresponsive or anergic. Anergy would affect the ability of DETC to proliferate and secrete factors during normal homeostasis and wound repair. Cross-talk between DETC and keratinocytes will be examined during type 2 diabetes to identify whether keratinocytes play a role in the suppression of DETC. Finally, two approaches will be taken to restore normal DETC activation in diabetic mice. First, the DETC will be targeted by treating mice with IL-2 cytokine therapy to restore DETC activation. The second approach involves improving insulin responsiveness to allow the keratinocytes to normalize, which may indirectly restore DETC function. Defining the impact of type 2 diabetes on T cell- epithelial cell interactions will greatly advance our knowledge of how this condition may lead to immune dysfunction. This will lead to the development of novel strategies to promote wound repair and other complications of diabetes. PUBLIC HEALTH RELEVANCE: T cells in the skin are stimulated by damaged keratinocytes to produce growth factors important for wound repair. Chronic non-healing wounds are a serious complication of diabetes with devastating consequences. The goal of our research is to determine how type 2 diabetes alters T cell survival and function in the epithelia and whether this process can be reversed therapeutically to promote healing of chronic wounds.

描述（由申请人提供）：糖尿病足溃疡是1型和2型糖尿病常见的令人衰弱的并发症。对研究的迫切需要，可以确定糖尿病如何影响皮肤等上皮组织中细胞细胞相互作用，这些相互作用非常容易受到损害。鼠皮34个T细胞，也称为树突状表皮T细胞（DETC），在皮肤稳态和伤口修复中起作用。激活角质形成细胞和反应开发的复杂串扰是由受体表达和生长因子产生介导的。我们的长期目标是确定糖尿病如何对免疫系统产生负面影响，特别关注上皮T细胞群体。该应用程序将检查2型糖尿病如何改变开发的生存和功能，以及是否可以通过治疗方法逆转。起作用的假设是，胰岛素耐药的角质形成细胞会长期刺激发病，从而使DETC凋亡并最终刺激。该假设是基于初步结果，该结果表明，糖尿病皮肤中发病和角质形成细胞之间的正常串扰。提出了以下特定目的：（1）确定为什么在2型糖尿病的小鼠皮肤中降低了DETC，（2）确定角质细胞-DETC交叉词对糖尿病小鼠中的DETC功能障碍的贡献，以及（3）恢复糖尿病小鼠中的发病率和功能。一旦我们确定了如何在糖尿病小鼠皮肤中抑制开发物，我们可能能够恢复激活并利用其伤口愈合潜力。这些特定目标将通过检查糖尿病皮肤的发病数量如何减少以及剩余的开发物在功能无反应或厌食的情况下测试。反应会影响开发在正常稳态和伤口修复期间增殖和分泌因素的能力。在2型糖尿病期间，将检查开特和角质形成细胞之间的串扰，以识别角质形成细胞是否在抑制开特中起作用。最后，将采用两种方法来恢复糖尿病小鼠中正常的DETC激活。首先，将通过使用IL-2细胞因子疗法治疗小鼠来恢复DETC激活来实现DETC。第二种方法涉及提高胰岛素反应能力以使角质形成细胞正常化，这可能会间接恢复DETC功能。定义2型糖尿病对T细胞上皮细胞相互作用的影响将大大提高我们对这种病如何导致免疫功能障碍的了解。这将导致发展新型策略，以促进伤口修复和其他并发症的糖尿病并发症。公共卫生相关性：皮肤中的T细胞受到受损的角质形成细胞的刺激，以产生对伤口修复重要的生长因子。慢性非愈合伤口是具有毁灭性后果的糖尿病的严重并发症。我们研究的目的是确定2型糖尿病如何改变上皮中T细胞的存活和功能，以及该过程是否可以通过治疗方法逆转以促进慢性伤口的愈合。