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:
    8018040
  • 负责人:
  • 金额:
    $ 37.22万
  • 依托单位:
  • 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 2014-01-31
  • 项目状态:
    已结题

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型糖尿病常见的衰弱并发症。迫切需要研究确定糖尿病如何影响上皮组织(如皮肤)中的细胞-细胞相互作用,这些组织非常容易受到损伤。小鼠皮肤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。活化的角质形成细胞和响应的DETC之间的复杂的相互作用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。本申请将研究2型糖尿病如何改变DETC的生存和功能,以及是否可以通过治疗逆转。工作假设是DETC长期受到胰岛素抗性角质形成细胞的刺激,导致DETC凋亡并最终无反应性。这一假设是基于初步的结果,这表明,正常的串扰之间的DETC和角质形成细胞在糖尿病皮肤改变。提出了以下具体目标:(1)确定为什么DETC在患有2型糖尿病的小鼠的皮肤中减少,(2)确定角质形成细胞-DETC串扰对糖尿病小鼠中DETC功能障碍的贡献,以及(3)恢复糖尿病小鼠中的DETC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,我们就有可能恢复激活并利用它们的伤口愈合潜力。将通过检查糖尿病皮肤中DETC数量如何下降以及剩余的DETC是否功能性无反应或无反应性来测试这些特定目标。无反应性会影响DETC在正常稳态和创伤修复过程中增殖和分泌因子的能力。将在2型糖尿病期间检查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DETC的抑制中发挥作用。最后,将采取两种方法来恢复糖尿病小鼠中的正常DETC激活。首先,通过用IL-2细胞因子疗法治疗小鼠以恢复DETC活化来靶向DETC。第二种方法涉及改善胰岛素反应性以使角质形成细胞正常化,这可能间接恢复DETC功能。确定2型糖尿病对T细胞-上皮细胞相互作用的影响将大大推进我们对这种情况如何导致免疫功能障碍的认识。这将导致开发新的策略来促进伤口修复和糖尿病的其他并发症。公共卫生相关性:皮肤中的T细胞受到受损角质细胞的刺激,产生对伤口修复很重要的生长因子。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。我们研究的目的是确定2型糖尿病如何改变上皮细胞中T细胞的存活和功能,以及这一过程是否可以在治疗上逆转,以促进慢性伤口的愈合。

项目成果

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JULIE M JAMESON其他文献

JULIE M JAMESON的其他文献

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{{ truncateString('JULIE M JAMESON', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 37.22万
  • 项目类别:
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:
    8208195
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
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
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
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:
    8420547
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
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:
    8281777
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
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:
    8520631
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
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:
    7758180
  • 财政年份:
    2009
  • 资助金额:
    $ 37.22万
  • 项目类别:
Gamma Delta T cell and keratinocyte cross-talk in diabetic wounds
糖尿病伤口中的 Gamma Delta T 细胞和角质形成细胞的相互作用
  • 批准号:
    7140624
  • 财政年份:
    2005
  • 资助金额:
    $ 37.22万
  • 项目类别:
Gamma Delta T cell and keratinocyte cross-talk in diabetic wounds
糖尿病伤口中的 Gamma Delta T 细胞和角质形成细胞的相互作用
  • 批准号:
    7014442
  • 财政年份:
    2005
  • 资助金额:
    $ 37.22万
  • 项目类别:

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