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: 7215158
• 负责人: Marjana Tomic-Canic
• 金额: $ 32.64万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215158
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Affect; Age; Area; Behavior; Biological; Biological Models; Blood Vessels; Chronic; Clinical; Complex; Country; Cutaneous; Deposition; Dermis; Development; Differentiation and Growth; Discipline of Nursing; Disease; EGF gene; Enzyme Inhibitor Drugs; Epidermis; Event; FGF7 gene; Gene Expression; Gene Targeting; Genes; Glucocorticoids; Goals; Growth Factor; Healed; Health; Histologic; Homeostasis; Hormone Receptor; Hormones; Human; Immune response; Immune system; Impaired wound healing; Individual; Interleukin-1; Knowledge; Laboratories; Lead; Ligands; Maps; Measures; Mediating; Medicine; Methods; Modeling; Molecular; Molecular Models; Monitor; Organ Culture Techniques; Pathogenesis; Pathway interactions; Patients; Process; Production; Proteins; Regulation; Regulator Genes; Regulatory Pathway; Research; Retinoids; Role; Scientist; Signal Pathway; Signal Transduction; Skin; Specific qualifier value; Specificity; Structure; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Ulcer; Vascular Permeabilities; Vitamins; Wound Healing; angiogenesis; base; cell type; cytokine; healing; immunocytochemistry; insight; keratinocyte; keratinocyte growth factor; migration; new technology; research study; response; size; tool; wound

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800多万人。作为一名具有护理背景的基础科学家，我致力于我的大部分研究，以了解协调表皮伤口愈合复杂过程的调节机制。这项建议侧重于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因子对伤口愈合影响的知识包括许多信息，每个信息集中在特定的单个基因或调节因子上，而没有定义全球图景。人们对调控因子及其靶基因的相互联系、它们之间的相互作用以及引导角质形成细胞完成其关键任务之一-伤口愈合的功能同步知之甚少。 例如，我们已经发现糖皮质激素，表皮生长、分化和动态平衡的重要调节者，抑制伤口愈合和免疫反应。我们发现，它们的生物学效应是通过一种特定的分子机制来介导的，该机制可以阻断另一组伤口愈合调节因子的信号，如肿瘤坏死因子/表皮生长因子等促炎性细胞因子/生长因子。为了开发更有效的治疗慢性伤口的方法，同时将副作用降至最低，这是我的长期目标，我们首先需要了解在正常愈合的表皮中，是什么调节了这一过程。 为了实现这一目标，我们利用人体皮肤器官培养和基因芯片全球转录分析的新技术，开发了创伤愈合模型系统。具体地说，我们将：1.通过基因表达的变化来确定和表征在伤口愈合过程中发生在表皮中的过程和分子事件；2.确定糖皮质激素和维甲酸如何调节参与伤口愈合过程的表皮基因；3.探索局部激素产生在伤口愈合过程中的可能性和作用。 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。这一知识应作为确定慢性伤口的原因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的基础。

项目成果

Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers.

• DOI: 10.1111/wrr.12142
• 发表时间: 2014-03
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Stojadinovic O;Pastar I;Nusbaum AG;Vukelic S;Krzyzanowska A;Tomic-Canic M
• 通讯作者: Tomic-Canic M

Role of keratinocytes in healing of chronic wounds.

• 发表时间: 2008
• 期刊: Surgical technology international
• 作者: I. Pastar;Olivera Stojadinović;M. Tomic-Canic

GENE PROFILING: IMPLICATIONS IN DERMATOLOGY.

基因分析：对皮肤病学的影响。

• DOI: 10.1586/17469872.2.6.763
• 发表时间: 2007
• 期刊: Expert review of dermatology
• 作者: Blumenberg,Miroslav;Tomic-Canic,Marjana
• 通讯作者: Tomic-Canic,Marjana

A gene signature of nonhealing venous ulcers: potential diagnostic markers.

• DOI: 10.1016/j.jaad.2008.07.018
• 发表时间: 2008-11
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Charles CA;Tomic-Canic M;Vincek V;Nassiri M;Stojadinovic O;Eaglstein WH;Kirsner RS
• 通讯作者: Kirsner RS

Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3β/β-catenin Pathway to Inhibit Wound Closure.

• DOI: 10.1016/j.jid.2016.11.036
• 发表时间: 2017-05
• 期刊: The Journal of investigative dermatology
• 作者: Jozic I;Vukelic S;Stojadinovic O;Liang L;Ramirez HA;Pastar I;Tomic Canic M
• 通讯作者: Tomic Canic M