Epidermal Genes and Their Regulators in Wound Healing

描述（由申请人提供）： 慢性和急性伤口愈合障碍是一个严重的健康问题，影响到该国800多万人。作为一名具有护理背景的基础科学家，我将研究的主要部分用于了解协调表皮伤口愈合复杂过程的调节机制。该提案的重点是了解表皮基因及其产物在皮肤伤口愈合中的作用和调控。目前关于表皮基因调节剂对伤口愈合的影响的知识由信息补丁组成，每个信息补丁都集中在特定的单个基因或调节剂上，而没有定义全局图像。很少有人知道的调控和他们的目标基因的相互联系，他们的相互作用和同步功能，导致角质形成细胞通过他们的重要任务之一-伤口愈合。 例如，我们已经发现糖皮质激素，表皮生长、分化和稳态的重要调节剂，抑制伤口愈合和免疫应答。我们发现，它们的生物学效应是通过一种特定的分子机制介导的，该机制阻断了另一组伤口愈合调节剂，促炎细胞因子/生长因子，如TNF/EGF的信号。为了开发更有效的慢性伤口治疗方法，同时最大限度地减少副作用，这是我的长期目标，我们需要首先了解在正常愈合的表皮中是什么调节这一过程。 为了实现这一目标，我们已经开发了一个伤口愈合模型系统，使用器官培养的人皮肤和新技术的全球转录分析的基因阵列。具体来说，我们将：1。通过分析基因表达的变化来鉴定和表征表皮中伤口愈合期间发生的过程和分子事件; 2.定义糖皮质激素和类维生素A如何调节参与伤口愈合过程的表皮基因;以及3.探索伤口愈合过程中局部激素产生的可能性并确定其作用。 从这些实验中获得的知识和见解将为我们提供表皮正常伤口愈合过程的全球转录图谱。这些知识应该作为确定慢性伤口原因的基础，并最终在分子水平上开发出更好的治疗方法，用于人类伤口。

DESCRIPTION (provided by applicant): Chronic and acute wound healing disorders represent a serious health problem that affects more than 8 million people in this country. As a basic scientist with a nursing background, I am devoting a major portion of my research to the understanding of the regulatory mechanisms coordinating the complex process of wound healing in the epidermis. This proposal focuses on understanding the role and regulation of epidermal genes and their products in cutaneous wound healing. Current knowledge of the effect of epidermal gene regulators on wound healing consists of patches of information, each focused on a specific individual gene or regulator, without defining the global picture. Very little is known about the interconnectedness of regulators and their target genes, their interactions and synchronization of functions that lead keratinocytes through one of their vital tasks - wound healing. For example, we have found that glucocorticoid hormones, important regulators of epidermal growth, differentiation and homeostasis, inhibit wound healing and immune responses. We found that their biological effects are mediated through a specific molecular mechanism that blocks the signals of another group of wound healing regulators, proinfiammatory cytokines/growth factors, such as TNF/EGF. In order to develop more effective treatments for chronic wounds, while minimizing side effects, which is my long-term goal, we need to understand first what regulates this process in normally healing epidermis. To achieve this goal, we have developed a wound healing model system using organ cultures of human skin and the novel technology of global transcriptional analysis by gene arrays. Specifically, we shall: 1. identify and characterize the processes and molecular events that occur during wound healing in epidermis by profiling changes in gene expression; 2. define how glucocorticoids and retinoids regulate the epidermal genes that participate in the wound healing process; and 3. explore the possibility and define the role of local hormone production during wound healing. The knowledge and insights gained from these experiments will provide us with a global transcriptional map of the normal wound healing process in epidermis. This knowledge should serve as a basis for determining the causes of chronic wounds and ultimately developing better treatments derived at the molecular level for use in human wounds.