Transcriptional Co-regulators in Epidermis

表皮的转录协同调节因子

• 批准号: 7903497
• 负责人: Bogi Andersen
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903497
• 关键词: Award; Basal Cell; Binding; Binding Sites; Biochemical; Bioinformatics; Biological Assay; Cell-Cell Adhesion; Cellular biology; Chromatin; Cloning; Complex; DNA-Binding Proteins; Defect; Development; Disease; Drosophila genus; Employee Strikes; Epidermis; Epithelial; Funding; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; In Vitro; Inflammatory; Inherited; Investigation; Knockout Mice; LIM Domain; Link; Lipids; Mediating; Methods; Mus; Mutagenesis; Peptide Hydrolases; Permeability; Premature Infant; Promoter Regions; Proteins; Public Health; Regulation; Research; Role; Site; Skin; Staging; Stratum Granulosum; Structural Protein; System; Testing; Trans-Activators; Transactivation; Transcriptional Regulation; base; chromatin immunoprecipitation; cofactor; fly; follow-up; in vivo; innovation; keratinocyte; mouse model; postnatal; programs; protein protein interaction; skin disorder; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of our research program is to understand transcriptional control of epidermal development and differentiation within the epidermis. One critical function of the epidermis is to form an effective permeability barrier; defective epidermal barrier contributes to many skin diseases. The formation of the barrier, which is intricately linked to the terminal differentiation of epidermal keratinocytes, depends on structural proteins, proteases, lipid composition and cell-cell adhesion in the granular layer of the epidermis. While we have gained significant understanding of the cell biology of the barrier, much less is known about the mechanisms that control its formation. In particular, we do not understand well the transcriptional control that underlies the coordinated expression multiple genes encoding barrier components. In the last funding period of this award, we discovered the Grainyhead-like transcription factor Grainyhead-like Epithelial Transactivator 1 (Get1/Grhl3) based on its interaction with the LIM-only factor LMO4. During development, both Get1 and LMO4 are expressed in the developing epidermis, suggesting a role in epidermal formation. Deletion of the Get1 gene leads to alterations in the expression of multiple genes linked to terminal differentiation and barrier formation of the epidermis. Furthermore, simultaneous deletion of both Get1 and LMO4 leads to a more severe defect in terminal differentiation, indicating that we have identified key transcription factors for control of terminal differentiation and barrier formation. Based on these findings we hypothesize that Get1 directly regulates multiple terminal differentiation genes in a stage-specific manner, and that Get1 forms a complex with LMO4 to regulate at least a subset of these genes. In this renewal application, we propose three Specific Aims: 1) to determine the mechanisms underlying deregulation of multiple terminal differentiation genes in Get1 knockout mice; 2) to define the temporal requirement for Get1 in regulation of epidermal terminal differentiation; and 3) to determine whether Get1 and LMO4 act in a complex to regulate terminal differentiation of the epidermis. These investigations will enhance our understanding of defective epidermal barrier formation, and may aid the discovery of treatment options. Defective skin barrier is a significant public health problem that occurs in several inherited and acquired diseases of the skin, as well as in premature infants.

描述（由申请人提供）：我们研究计划的长期目标是了解表皮发育和表皮内分化的转录控制。表皮的一个关键功能是形成有效的渗透屏障;缺陷的表皮屏障导致许多皮肤疾病。与表皮角质形成细胞的终末分化密切相关的屏障的形成取决于表皮颗粒层中的结构蛋白、蛋白酶、脂质组成和细胞-细胞粘附。虽然我们已经对屏障的细胞生物学有了很大的了解，但对控制其形成的机制知之甚少。特别是，我们不了解以及协调表达的多个基因编码的屏障组件的转录控制。在该奖项的最后一个资助期内，我们发现了Grainyhead样转录因子Grainyhead样上皮反式激活因子1（Get 1/Grhl 3），基于其与LIM唯一因子LMO 4的相互作用。在发育过程中，Get 1和LMO 4都在发育中的表皮中表达，表明在表皮形成中起作用。Get 1基因的缺失导致与表皮的终末分化和屏障形成相关的多个基因的表达改变。此外，Get 1和LMO 4的同时缺失导致终末分化中更严重的缺陷，表明我们已经确定了控制终末分化和屏障形成的关键转录因子。基于这些发现，我们假设Get 1直接调节多个终末分化基因的阶段特异性的方式，和Get 1形成一个复合物与LMO 4调节至少一个子集的这些基因。在该更新申请中，我们提出了三个特定目的：1）确定Get 1敲除小鼠中多个终末分化基因失调的潜在机制; 2）定义Get 1在调节表皮终末分化中的时间要求; 3）确定Get 1和LMO 4是否以复合物的形式调节表皮终末分化。这些调查将提高我们对缺陷性表皮屏障形成的理解，并可能有助于发现治疗方案。皮肤屏障缺陷是一个重要的公共卫生问题，发生在几种遗传性和获得性皮肤疾病以及早产儿中。