Epidermal Genes and Their Regulators in Wound Healing

伤口愈合中的表皮基因及其调控因子

• 批准号: 7168304
• 负责人: Marjana Tomic-Canic
• 金额: $ 24.44万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7168304
• 关键词: biological signal transduction; cell differentiation; clinical research; enzyme inhibitors; gene expression; glucocorticoids; hormone biosynthesis; human tissue; immunocytochemistry; keratinocyte; microarray technology; organ culture; retinoids; skin; transcription factor; vitamin receptor; wound healing

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.

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，影响着这个国家超过 800 万人。作为一名具有护理背景的基础科学家，我的研究的主要部分致力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节。目前关于表皮基因调节因子对伤口愈合影响的知识由大量信息组成，每个信息都集中在特定的个体基因或调节因子上，而没有定义全局情况。对于调节因子及其靶基因的相互联系、它们的相互作用以及引导角质形成细胞完成其重要任务之一——伤口愈合的功能同步性，人们知之甚少。 例如，我们发现糖皮质激素是表皮生长、分化和体内平衡的重要调节剂，会抑制伤口愈合和免疫反应。我们发现它们的生物效应是通过一种特定的分子机制介导的，该机制阻断另一组伤口愈合调节剂、促炎细胞因子/生长因子（例如 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调节这一过程的因素。 为了实现这一目标，我们利用人体皮肤器官培养物和基因阵列全局转录分析新技术开发了伤口愈合模型系统。具体来说，我们应该： 1. 通过分析基因表达的变化来识别和表征表皮伤口愈合过程中发生的过程和分子事件； 2. 明确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； 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局转录图。这些知识应作为确定慢性伤口原因的基础，并最终开发出在分子水平上用于人类伤口的更好治疗方法。