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

项目总结/摘要 正常的皮肤功能被认为取决于皮脂腺（SG），这是典型的成对附属物， 与毛囊有关的SGs的主要目的是分泌皮脂，一种富含脂质的物质，作用于 调节皮肤屏障功能和水合作用，同时可能具有抗氧化和抗微生物 特性.异常的SG与皮肤病理学有关，如痤疮和瘢痕性脱发，但 它们在疾病中的功能作用仍不清楚。 尽管许多基因和信号通路与维持SGs有关，但很少有研究表明， 表征了这些因子调节SG干细胞分化的机制，以及它们是否 影响是直接或间接的。我们以前的研究发现Notch信号同时发挥双重作用， 对SG的相反作用：尽管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SG。我们 进一步观察到，PPARγ/K5双阳性群体可能作为直接祖细胞， 在腺体中产生分化的皮脂腺细胞。 这项提案旨在确定一些复杂的因素，调节SG干细胞，并测试 需要SG来维持正常的皮肤功能。在目标1中，我们将研究Notch如何直接 促进SG干细胞分化，并评估可能调节SG功能的新基因。在目标2中， 将决定Notch依赖性表皮分化的破坏如何导致SG扩大。在目标3中， 我们将评估在整个皮肤中删除SG的后果。这些研究将 表征SG干细胞是如何调节的，无论是局部的还是远距离的，并可能发现新的 这些腺体的功能。这些研究建立在新兴的概念，不同的细胞亚群， 皮肤中的细胞间通过各种信号相互联系和沟通 线索

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.