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细胞的终末分化和T细胞的发育和稳态所需。飞艇-1是 也在上皮细胞中表达。我们最近创造了一种角质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， 头发周期延迟我们的长期目标是利用表皮对Blimp-1的这种需求， 了解更多关于控制滤泡间分化基因调控的分子机制 角质形成细胞、皮脂腺细胞和毛囊的内根鞘细胞。 在本建议中，我们将重点关注IFE的颗粒层/角质层过渡的缺陷 图1示出了在具有Blimp-1（CKO）的角质形成细胞特异性条件性敲除的小鼠中的角质形成细胞中的细胞凋亡的方法。我们将 进行生物化学、免疫荧光和电子显微镜研究，以彻底表征 发育缺陷然后，我们将对来自对照和CKO的细胞进行全局基因表达研究 小鼠来鉴定并随后验证颗粒层细胞中的基因表达程序， Blimp-1。这项工作将为后续研究提供基础，以确定，无论是机械和 在功能上是颗粒层/角质层转变的关键调节剂。这些信息将有助于 了解影响正常角质层形成的疾病， 开发药物以改变失调的分化。 博士Calame有资格作为指南中的类别#2作为一个既定的研究者，没有以前的工作 在皮肤病中。本P&F研究将使用芯A和B。

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.