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

我们的实验室研究了一种称为B淋巴细胞诱导成熟的转录抑制因子的作用 蛋白-1(Blimp-1)。BLIMP-1控制B和T淋巴细胞基因调控的关键级联反应 B细胞的终末分化和T细胞的发育和内稳态所必需的。软式飞艇-1是 在上皮细胞中也有表达。我们最近创造了角质形成细胞特异性缺失的小鼠 BLIMP-1使用角蛋白-14 Cre小鼠。这些小鼠的颗粒层/角质层存在缺陷。 角质层的过渡和形成，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 进一步了解控制卵泡间分化的基因调控的分子机制 毛囊的角质形成细胞、皮脂细胞和内根鞘细胞。 在这项建议中，我们将集中于IFE的颗粒层/角质层过渡的缺陷。 角质形成细胞特异性条件性敲除Blimp-1(CKO)小鼠的角质形成细胞。我们会 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，我们将对对照组和CKO的细胞进行全局基因表达研究 小鼠识别并随后验证颗粒层细胞中受调控的基因表达程序 被Blimp-1。这项工作将为后续研究提供基础，以机械地和 从功能上讲，是颗粒层/角质层过渡的关键调节因子。这些信息将有助于 了解影响正常角膜层形成的疾病，并可能为 开发药物以改变错误调节的分化。 Calame博士符合指南中第2类的资格，是一名没有任何工作经验的既定研究人员 在皮肤病方面。这项P&F研究将使用A和B岩芯。

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.