Mechanisms of HOX gene function during wound repair

描述（由申请人提供）：本提案概述了一种使用糖尿病小鼠模型阐明Hox 3组基因在正常愈合和受损愈合的组织重塑过程中的功能机制的策略。拟议的研究集中在HoxaS上，扩展了我们以前对促进血管生成和伤口修复的相关HoxbS和HoxdS基因的工作。Kim在过去一年半的工作表明，在伤口修复中，HoxaS是一个比HoxdS更有效的因子，并且这一特征背后的一些细胞机制包括HoxaS诱导角质形成细胞迁移的能力，而HoxdS则没有。由于HoxaS似乎激活了与HoxbS或HoxdS不同的靶基因，Kim将研究这些基因是否是HoxaS的直接靶点，并使用染色质免疫沉淀法鉴定和表征血管生成和伤口修复过程中HoxS组基因的其他直接靶点。最后，为了更好地了解糖尿病环境中受损伤口修复的细胞病理学，Kim将测试在伤口愈合中具有既定作用的细胞因子是否正常诱导HoxS组基因的表达，以及这些细胞因子的伤口愈合功能是否依赖于这些基因的激活。

DESCRIPTION (provided by applicant): This proposal outlines a strategy to elucidate the mechanism of function of Hox3-group genes during tissue remodeling in both normal healing and impaired healing using a diabetic mouse model. The proposed studies, focused on HoxaS, extend from our previous work on the related HoxbS and HoxdS genes which act to promote angiogenesis and wound repair. Kim's work, over the past year and a half, has shown that HoxaS is a more potent factor than HoxdS in wound repair, and that some of the cellular mechanisms which underlie this characteristic include the ability of HoxaS to induce keratinocyte migration, whereas HoxdS does not. As HoxaS appears to activate distinct target genes from HoxbS or HoxdS, Kim will investigate whether these genes are direct targets of HoxaS, as well as identify and characterize additional direct targets of HoxS-group genes during angiogenesis and wound repair using chromatin immunoprecipitation. Finally, in order to better understand the cellular pathology of impaired wound repair in the diabetic environment, Kim will test whether cytokines with established roles in wound healing normally act to induce expression of HoxS-group genes and whether the wound healing functions of these cytokines are dependent on the activation of these genes.