A Study of Biological Function of Basonuclin

碱性核蛋白的生物学功能研究

基本信息

批准号：
7579551
负责人：
GEORGE COTSARELIS
金额：
$ 39.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-10 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7579551
关键词：
Affect Age Area Basal cell carcinoma Biochemical Bioinformatics Biological Assay Biological Process Biology Breeding Burn injury CD34 gene Cell physiology Cells Cutaneous DNA-Directed RNA Polymerase Epidermal Growth Factor Receptor Epidermis Epithelial Epithelium Evaluation Excision Gene Expression Genes Genetic Transcription Goals Hair Hair follicle structure Hair shaft structure In Vitro Injury Knock-out Knockout Mice Link MAP Kinase Gene MAPK14 gene Maintenance Maps Mediator of activation protein Modeling Molecular Movement Mus Mutant Strains Mice Mutation Natural regeneration Pathway interactions Phenotype Proteins Recombinant DNA Research Role Skin Skin Aging Skin Cancer Stem cells Testing Thick Time Transforming Growth Factor alpha Wound Healing Zinc Fingers basonuclin in vivo inhibitor/antagonist keratinocyte migration null mutation receptor response restoration skin disorder skin regeneration stem cell biology transcription factor

项目摘要

Our long-term goal is to understand the role of the basonuclin gene in skin and hair follicle biology. Basonuclin (BNC1) is a zinc finger protein found in abundance in the keratinocytes of the epidermis and hair follicle. We believe that it coordinates activity of other genes through transcription factor activity. Our biochemical and bioinformatic studies show that BNC1 regulates transcription of genes in six different pathways. The BNC1 regulatory network is linked to pathways such as EGFR, p38 MAPK and TGFalpha. These genes control important cellular functions like proliferation, migration and differentiation. BNC1 is up-regulated in basal cell carcinoma (BCC). Our study of a Bnc1 knock out model suggests that it is required for hair follicle regeneration after hairplucking, and Bnc1-null mutation delays restoration of hair follicular stem cells after hairplucking. In this proposal, we will evaluate the role of Bnc-1 and Bnc-2 in skin regeneration, wound repair and hair follicle cycling. We will characterize how the Bnc1- null mutation affects hair regeneration, including determination of which cellular processes are affected by this mutation and what molecular perturbations are caused by Bnc1-null mutation. By examining Bnc-1 and Bnc-2 single and double knockout mice, we will assess the contribution of these genes to maintenance of epithelial stem cells in the bulge as well as the response of these cells to injury. Using mice that we have developed to study the fate of bulge stem cells, we will trace the movement and contribution of bulge cells in the Bnc mutant mice following hair plucking and skin injury. We will study the interaction of BNC with the EGFr pathway using mice with deleted receptors or mice expressing inhibitors of the EGFr pathway. Changes in proliferation, differentiation and migration will be assessed in both in vitro and in vivo assays. Overall, our research will discern the effect of deleting Bnc-1 and Bnc-2 in the cutaneous epithelium. The role of Bnc’s in the EGFr pathway will be discerned. The studies will impact on understanding stem cell biology and the role of Bnc’s in wound healing, hair cycling and skin regeneration.

我们的长期目标是了解基底核蛋白基因在皮肤和头发中的作用 Basonuclin (BNC1) 是一种在卵泡生物学中大量存在的锌指蛋白。我们认为它协调表皮和毛囊的角质形成细胞的活动。通过我们的生物化学和生物信息活性的其他基因。研究表明，BNC1 通过六种不同途径调节基因转录。 BNC1 调控网络与 EGFR、p38 MAPK 和 TGFalpha 等通路相关。这些基因控制重要的细胞功能，如增殖、迁移和 BNC1 在基底细胞癌 (BCC) 中表达上调。敲除模型表明，拔毛后毛囊再生需要它， Bnc1 缺失突变会延迟拔毛后毛囊干细胞的恢复。在本提案中，我们将评估 Bnc-1 和 Bnc-2 在皮肤中的作用我们将描述 Bnc1- 的再生、伤口修复和毛囊循环。无效突变影响毛发再生，包括确定哪种细胞过程受到这种突变的影响以及分子扰动是由什么引起的通过检查 Bnc-1 和 Bnc-2 单敲除和双敲除小鼠，我们发现 Bnc1 缺失突变。将评估这些基因对维持上皮干细胞的贡献使用我们拥有的小鼠来观察凸起以及这些细胞对损伤的反应。开发用于研究凸起干细胞的命运，我们将追踪其运动和 Bnc 突变小鼠在拔毛和皮肤损伤后凸出细胞的贡献。我们将使用缺失基因的小鼠研究 BNC 与 EGFr 通路的相互作用受体或表达 EGFr 通路抑制剂的小鼠的增殖变化，将在体外和体内测定中评估分化和迁移。总的来说，我们的研究将辨别删除 Bnc-1 和 Bnc-2 对皮肤上皮细胞中 Bnc 的作用将被识别。研究将有助于理解干细胞生物学和 BNC 在伤口中的作用愈合、毛发循环和皮肤再生。