Regulation of sebaceous gland stem cells and their differentiated progeny in the skin

项目摘要/摘要 我们的皮肤提供了一种屏障，保护我们免受环境的伤害。正常的皮肤功能被认为依赖于 在皮脂腺(SGS)上，皮脂腺是一对附属物，通常与毛囊相关。主 SGS的目的是分泌皮脂，一种作用于皮肤的富含脂肪的物质，调节屏障功能和 水合作用，同时可能具有抗氧化和抗微生物特性。异常的SGS已经被 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 目前仍不清楚。 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干细胞分化的具体机制，以及 无论这些影响是直接的还是间接的。我们之前的研究发现，Notch信号 同时对SGS施加相反的力量：而Notch直接促进SG干细胞分化， 这一途径也间接抑制表面毛囊间表皮的SGS。我们还观察到， PPARγ/K5双阳性群体可能识别导致 腺体内分化的皮脂细胞。 这项建议试图确定调控SG干细胞的一些复杂因素，以测试SGS的作用 在正常皮肤功能下，并确定PPARγ/K5双阳性群体是否显示干细胞 属性。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，我们将确定Notch如何间接抑制 SG分化，并测试EpiGen的上调是否在功能上与表皮的Notch破坏有关 通过SG扩展。在目标3中，我们将评估SG维护是否需要PPARγ，以及是否 表达这种转录因子的细胞可以作为SG干细胞。最后，我们将描述本地化的特征 PPARγ/K5双阳性细胞在正常人皮肤和病理皮肤中均有表达。总而言之，这些研究将 阐明SG干细胞是如何在局部和远程受到调控的，同时可能发现新的 SG在皮肤中的作用。

Project Summary / Abstract Our skin provides a barrier that protects us against the environment. 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 specific mechanisms by which these factors modulate SG stem cell differentiation, and whether these effects are direct or indirect. Our previous studies have found that Notch signaling simultaneously exerts opposing forces on SGs: Whereas Notch directly promotes SG stem cell differentiation, this pathway also indirectly suppresses SGs from the surface interfollicular epidermis. We also observed that a PPARγ/K5 double-positive population likely identifies 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, to test the role of SGs in normal skin function, and to determine whether the PPARγ/K5 double-positive population exhibits stem cell properties. 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 Notch also indirectly suppresses SG differentiation, and test whether upregulation of epigen functionally links Notch disruption in the epidermis with SG expansion. In Aim 3, we will assess whether PPARγ is required for SG maintenance, and whether cells expressing this transcription factor can act as SG stem cells. Finally, we will characterize the localization of PPARγ/K5 double-positive cells in both normal and pathological human skin. Altogether, these studies will elucidate how SG stem cells are regulated, both locally and from a distance, while potentially uncovering novel roles for SG function in the skin.