A Study of Biological Function of Basonuclin

碱性核蛋白的生物学功能研究

• 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
• 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

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basonuclin基因在皮肤和头发中的作用 卵泡生物学碱性核蛋白（BNC 1）是一种锌指蛋白，在哺乳动物中大量存在。 表皮和毛囊的角化细胞。我们认为它协调了 其他基因通过转录因子的活动。我们的生物化学和生物信息学 研究表明，BNC 1通过六种不同的途径调节基因的转录。的 BNC 1调控网络与EGFR、p38 MAPK和TGF α等通路相关。 这些基因控制重要的细胞功能，如增殖、迁移和 分化BNC 1在基底细胞癌（BCC）中表达上调。我们对Bnc 1的研究 敲除模型表明它是拔毛后毛囊再生所必需的， 而Bnc 1无效突变延迟了拔毛后毛囊干细胞的恢复。 在这个建议中，我们将评估BNC-1和BNC-2在皮肤中的作用， 再生、伤口修复和毛囊循环。我们将描述Bnc 1- 无效突变影响毛发再生，包括确定哪些细胞 过程受到这种突变的影响，以及什么样的分子扰动是由 bnc 1-无效突变。通过检测BNC-1和BNC-2单基因和双基因敲除小鼠， 将评估这些基因对维持上皮干细胞的贡献， 以及这些细胞对损伤的反应。利用我们现有的老鼠 为了研究隆突干细胞的命运，我们将追踪其运动， 在拔毛和皮肤损伤后的BNC突变小鼠中隆突细胞的贡献。 我们将使用缺失EGFr的小鼠研究BNC与EGFr通路的相互作用。 受体或表达EGFr途径抑制剂的小鼠。增殖的变化， 分化和迁移将在体外和体内测定中评估。 总的来说，我们的研究将辨别删除Bnc-1和Bnc-2在细胞中的作用。 皮肤上皮Bnc在EGFr途径中的作用将被识别。的 这些研究将对理解干细胞生物学和BNC在伤口中的作用产生影响， 愈合、毛发循环和皮肤再生。