Mechanisms for Impaired Diabetic Oral Wound Healing

项目摘要 愈合口腔伤口的能力是个人健康的一个重要方面，并且受到以下因素的负面影响： 糖尿病令人惊讶的是，关于糖尿病对口腔创伤分子事件的影响， 治愈我们最近发表的研究表明，转录因子叉头盒O1的激活 角质形成细胞中的Foxo1在创伤的再上皮化中起重要但令人惊讶的相反作用， 糖尿病和血糖正常的动物。初步数据显示，角质形成细胞促进结缔组织 在正常条件下通过FOXO 1依赖性机制愈合，但抑制结缔组织 在糖尿病伤口中形成。这项提案的目标是解开分子机制， FOXO 1差异激活角质形成细胞，以促进或抑制结缔组织愈合，这取决于 血糖正常或糖尿病状况。这些结果将确定FOXO 1如何成为一种重要的治疗药物， 促进糖尿病伤口愈合的靶点。目标1将建立机制，通过这些机制，两个关键FOXO 1 下游靶点（TGFβ1和MMP 9）在体外受糖尿病条件（高葡萄糖 和晚期糖基化终产物），并将结果与表皮 角质形成细胞目的2将建立角质形成细胞促进结缔组织愈合的机制 在血糖正常的伤口中以FOXO 1依赖的方式，但在糖尿病伤口中抑制FOXO 1。这些研究将 关注FOXO 1在组织角质形成细胞刺激成纤维细胞的因子表达中的影响 和内皮细胞，但在糖尿病条件下不能这样做。Aim 3的目标是实现 进行转化研究，并建立功能性的糖尿病治疗。他们将决定是否 FOXO 1下游靶点的调节逆转糖尿病损害的牙龈和皮肤愈合， FOXO 1是促进糖尿病愈合的良好治疗靶点。建议的研究得到大力支持 通过初步数据，将明确测试FOXO 1是否在受损的糖尿病口腔伤口中发挥核心作用。 愈合，并将提供基础，为未来的研究，通过建立其抑制是否具有治疗 值

Project Summary The ability to heal oral wounds is an important aspect of an individual's health and is negatively affected by diabetes. Surprisingly little is known about the impact of diabetes on the molecular events of oral wound healing. Our recently published studies demonstrate that activation of the transcription factor forkhead box O1 (Foxo1) in keratinocytes plays important but surprisingly, opposite roles in re-epithelialization of wounds in diabetic and normoglycemic animals. Preliminary Data shows that keratinocytes promote connective tissue healing under normal conditions through a FOXO1 dependent mechanism but inhibit connective tissue formation in diabetic wounds. The goal of this proposal is to unravel the molecular mechanisms through which FOXO1 differentially activates keratinocytes to promote or inhibit connective tissue healing depending upon normoglycemic or diabetic conditions. The results will establish how FOXO1 may be an important therapeutic target in promoting wound healing in diabetes. Aim 1 will establish mechanisms through which two key FOXO1 downstream targets (TGFβ1 and MMP9) are inversely modulated by diabetic conditions in vitro (high glucose and advanced glycation end products) in gingival keratinocytes and compare the results with epidermal keratinocytes. Aim 2 will establish mechanisms through which keratinocytes enhance connective tissue healing in a FOXO1 dependent manner in normoglycemic wounds but inhibit it in diabetic wounds. These studies will focus on the impact of FOXO1 in organizing the expression of factors by keratinocytes that stimulate fibroblasts and endothelial cells in normal conditions but fail to do this in diabetic conditions. The goal of Aim 3 is to carry out translational studies and establish functional to rescue diabetic healing. They will determine whether modulation of FOXO1 downstream targets reverses diabetes impaired gingival and dermal healing and whether FOXO1 is a good therapeutic target to improve diabetic healing. The proposed studies are strongly supported by Preliminary Data, will definitively test whether FOXO1 plays a central role in impaired diabetic oral wound healing and will provide the basis for future studies by establishing whether its inhibition has therapeutic value.