Role of B Lymphocyte Induced Maturation Protein-1 (Blimp-1) in the Epidermis

B 淋巴细胞诱导成熟蛋白 1 (Blimp-1) 在表皮中的作用

• 批准号: 7454977
• 负责人: KATHRYN L. CALAME
• 金额: $ 3.91万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454977
• 关键词: Affect; B lymphocyte-induced maturation protein 1; B-Cell Development; Biochemical; Biochemistry; Categories; Cells; Defect; Development; Disease; Electron Microscopy; Electrons; Epidermis; Epithelial Cells; Gene Expression; Gene Expression Regulation; Goals; Guidelines; Hair; Hair follicle structure; Homeostasis; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Knock-out; Laboratory Study; Learning; Lymphocyte; Messenger RNA; Microscopic; Molecular; Mus; Plant Roots; Proteins; Qualifying; Range; Research Personnel; Role; Sebum; Stratum Granulosum; Stratum corneum; T-Lymphocyte; Work; base; drug development; keratin 14, K14; keratinocyte; keratinocyte differentiation; programs; skin disorder

Our laboratory studies the role of a transcriptional represser called B Lymphocyte Induced Maturation Protein -1 (Blimp-1). Blimp-1 controls critical cascades of gene regulation in B and T lymphocytes and is required for terminal differentiation of B cells and for development and homeostasis of T cells. Blimp-1 is also expressed in epithelial cells. We have recently created mice with a keratinocyte-specific deletion of Blimp-1 using keratin-14 Cre mice. These mice have defects in the granular layer/stratum corneum transition and formation of the stratum corneum, defects in sebocyte differentiation and sebum release and delayed hair cycle. Our long-range goal is to take advantage of this requirement for Blimp-1 in epidermis to learn more about molecular mechanisms of gene regulation that control differentiation of interfollicular keratinocytes, sebocytes and inner root sheath cells of the hair follicle. In this proposal, we will focus on the defect in the granular layer/stratum corneum transition of IFE keratinocytes in mice having a keratinocyte-specific conditional knock-out of Blimp-1 (CKO). We will perform biochemical, immunofluorescence and electron microscopic studies to thoroughly characterize the developmental defect. Then we will perform global gene expression studies on cells from control and CKO mice to identify and subsequently verify gene expression programs in granular layer cells that are regulated by Blimp-1. This work will provide the basis for subseuent studies to identify, both mechanistically and functionally, critical regulators of the granular layer/stratum corneum transition. Such information will aid in understanding diseases affecting the formation of normal stratum corneus and may provide targets for the development of drugs to modify misregulated differentiation. Dr. Calame qualifies as Category #2 in the Guidelines as an Established Investigator with no previous work in skin diseases. This P&F study will use Cores A and B.

我们的实验室研究称为 B 淋巴细胞诱导成熟的转录抑制因子的作用 蛋白质-1（Blimp-1）。 Blimp-1 控制 B 和 T 淋巴细胞中基因调控的关键级联， B 细胞的终末分化以及 T 细胞的发育和稳态所需的。 Blimp-1 是 也在上皮细胞中表达。我们最近创造了具有角质形成细胞特异性缺失的小鼠 Blimp-1 使用 keratin-14 Cre 小鼠。这些小鼠的颗粒层/角质层有缺陷 角质层的转变和形成、皮脂细胞分化和皮脂释放的缺陷以及 头发周期延迟。我们的长期目标是利用表皮中 Blimp-1 的这一要求 了解更多关于控制卵泡间分化的基因调控分子机制 毛囊的角质形成细胞、皮脂细胞和内根鞘细胞。 在本提案中，我们将重点关注IFE颗粒层/角质层过渡的缺陷 具有角质形成细胞特异性条件性敲除 Blimp-1 (CKO) 的小鼠的角质形成细胞。我们将 进行生化、免疫荧光和电子显微镜研究，以彻底表征 发育缺陷。然后我们将对对照和 CKO 细胞进行全局基因表达研究 小鼠识别并随后验证受调节的颗粒层细胞中的基因表达程序 由 Blimp-1 提供。这项工作将为后续研究提供基础，以从机制和机制上识别 在功能上，颗粒层/角质层过渡的关键调节剂。此类信息将有助于 了解影响正常角质层形成的疾病，并可能为治疗提供目标 开发药物来改变失调的分化。 Calame 博士作为没有任何工作经验的资深研究者，符合指南中的第 2 类资格 在皮肤病中。本 P&F 研究将使用核心 A 和 B。