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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

基本信息

批准号：
8208195
负责人：
JULIE M JAMESON
金额：
$ 28.12万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2012-08-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208195
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 Health 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 TNF gene 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 receptor receptor expression repaired reproductive response

项目摘要

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 型糖尿病常见的一种使人衰弱的并发症。迫切需要研究确定糖尿病如何影响上皮组织（例如皮肤）中的细胞间相互作用，这些组织非常容易受到损伤。鼠皮肤 34 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发挥作用。激活的角质形成细胞和响应的 DETC 之间复杂的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。该应用将研究 2 型糖尿病如何改变 DETC 的存活和功能，以及是否可以通过治疗逆转这种情况。工作假设是 DETC 受到胰岛素抵抗角质形成细胞的长期刺激，导致 DETC 凋亡并最终无反应性。这一假设基于初步结果，该结果表明 DETC 和角质形成细胞之间的正常交互作用在糖尿病皮肤中发生了改变。提出以下具体目标：（1）确定为什么 DETC 在 2 型糖尿病小鼠的皮肤中减少，（2）确定角质形成细胞-DETC 串扰对糖尿病小鼠 DETC 功能障碍的影响，以及（3）恢复糖尿病小鼠中 DETC 的数量和功能。一旦我们确定了 DETC 在糖尿病小鼠皮肤中是如何被抑制的，我们也许能够恢复激活并利用它们的伤口愈合潜力。这些具体目标将通过检查糖尿病皮肤中 DETC 数量如何下降以及剩余的 DETC 是否变得功能上无反应或无反应来进行测试。无反应会影响 DETC 在正常体内平衡和伤口修复过程中增殖和分泌因子的能力。在 2 型糖尿病期间将检查 DETC 和角质形成细胞之间的串扰，以确定角质形成细胞是否在抑制 DETC 中发挥作用。最后，将采取两种方法来恢复糖尿病小鼠的正常 DETC 激活。首先，通过用 IL-2 细胞因子疗法治疗小鼠来恢复 DETC 的激活，从而靶向 DETC。第二种方法涉及改善胰岛素反应性，使角质形成细胞正常化，这可能会间接恢复 DETC 功能。明确 2 型糖尿病对 T 细胞-上皮细胞相互作用的影响将极大地增进我们对这种情况如何导致免疫功能障碍的了解。这将导致促进伤口修复和糖尿病其他并发症的新策略的开发。公共健康相关性：皮肤中的 T 细胞受到受损角质形成细胞的刺激，产生对伤口修复至关重要的生长因子。慢性不愈合伤口是糖尿病的严重并发症，具有毁灭性的后果。我们研究的目标是确定 2 型糖尿病如何改变上皮细胞中 T 细胞的存活和功能，以及是否可以通过治疗逆转这一过程以促进慢性伤口的愈合。