Functional characterization of sebaceous gland stem cells and sebocytes in the skin

项目摘要/摘要 正常的皮肤功能被认为依赖于皮脂腺(SGS)，皮脂腺通常是成对的附件 与毛囊有关。SGS的主要目的是分泌皮脂，这是一种富含脂肪的物质，作用于 调节皮肤的屏障功能和水合作用，同时可能具有抗氧化和抗微生物作用 属性。异常的SGS与皮肤病理有关，如粉刺和疤痕脱发，但 它们在疾病中的功能作用尚不清楚。 尽管许多基因和信号通路与SGS的维持有关，但很少有研究 描述了这些因素调节SG干细胞分化的机制，以及它们的 影响是直接的或间接的。我们以前的研究发现，Notch信号同时施加双重 对SGS的相反作用：虽然Notch直接促进SG干细胞分化，但该途径也 通过调节表面毛囊间表皮的适当分化间接抑制SGS。我们 进一步观察到，PPARγ/K5双阳性群体可能是 在腺体中产生分化的皮脂细胞。 这项提案旨在确定调节SG干细胞的一些复杂因素，并测试 对SGS维持正常皮肤功能的要求。在目标1中，我们将研究Notch如何直接 促进SG干细胞分化，评估可能调节SG功能的新基因。在目标2中，我们 将决定Notch依赖的表皮分化的破坏如何导致SGS扩大。在《目标3》中， 我们将评估在整个皮肤中删除SGS的后果。总而言之，这些研究将 描述SG干细胞是如何在本地和远程调节的，并可能发现新的 这些腺体的功能。这些研究建立在一个新兴的概念上，即不同的细胞亚群 皮肤中的隔间错综复杂地联系在一起，并通过各种信号相互通信 暗示。

Project Summary / Abstract Normal skin function is thought to depend on sebaceous glands (SGs), which are paired appendages typically associated with hair follicles. The main purpose of SGs is to secrete sebum, a lipid-rich substance that acts on the skin to regulate barrier function and hydration, while possibly possessing anti-oxidant and anti-microbial properties. Aberrant SGs have been associated with skin pathologies such as acne and scarring alopecia, but their functional roles in disease remain unclear. Although numerous genes and signaling pathways have been implicated in maintaining SGs, few studies have characterized the mechanisms by which these factors modulate SG stem cell differentiation, and whether their effects are direct or indirect. Our previous studies have found that Notch signaling simultaneously exerts dual opposing effects on SGs: Whereas Notch directly promotes SG stem cell differentiation, this pathway also indirectly suppresses SGs by regulating proper differentiation in the surface interfollicular epidermis. We further observed that a PPARγ/K5 double-positive population likely serves as the immediate progenitors that give rise to differentiated sebocytes in the gland. This proposal seeks to identify some of the complex factors that regulate SG stem cells and to test the requirement for SGs in maintaining normal skin function. In Aim 1, we will examine how Notch directly promotes SG stem cell differentiation, and evaluate novel genes that may modulate SG function. In Aim 2, we will determine how disruption of Notch-dependent epidermal differentiation causes SGs to enlarge. In Aim 3, we will assess the consequences of deleting SGs throughout the skin. Altogether, these studies will characterize how SG stem cells are regulated, both locally and from a distance, and potentially uncover novel functions for these glands. These studies build upon the emerging concept that different cellular sub- compartments in the skin are intricately linked and communicate with each other through a variety of signaling cues.