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

皮肤皮脂腺干细胞及其分化后代的调节

基本信息

批准号：
10226584
负责人：
Sunny Y Wong
金额：
$ 34.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226584
关键词：
Acne Adult Affect Alopecia Antioxidants Attention Attenuated Behavior Biology Candidate Disease Gene Cell Compartmentation Cells Cicatrix Complement Complex Data Data Set Disease Environment Epidermal Growth Factor Receptor Epidermis Epithelial Epithelium Exhibits Foundations Functional disorder G Cells Genes Gland Goals Growth Factor Hair follicle structure Hormones Human Hydration status Hypersensitivity skin testing Kinetics Life Ligands Link Lipids Maintenance Outcome PPAR alpha PPAR gamma Pathologic Pathology Pathway interactions Phenocopy Play Population Property Regulation Role Sebaceous Gland Diseases Sebaceous Glands Sebum Signal Pathway Signal Transduction Skin Source Surface TTA System Testing Time Up-Regulation Water antimicrobial antimicrobial drug appendage base epigen experimental study keratin 5 notch protein novel progenitor promoter receptor skin barrier stem cell differentiation stem cells stemness transcription factor transcriptome sequencing

项目摘要

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.

项目概要/摘要我们的皮肤提供了保护我们免受环境侵害的屏障，正常的皮肤功能被认为取决于环境。皮脂腺（SG），是通常与毛囊相关的成对附属物。 SG 的目的是分泌皮脂，这是一种富含脂质的物质，作用于皮肤以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。与痤疮和疤痕性脱发等皮肤病理相关，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 SG 相关，但很少有研究表明描述了这些因子调节 SG 干细胞分化的具体机制，以及我们之前的研究发现这些影响是直接的还是间接的。同时对 SG 施加相反的作用力：除了 Notch 直接促进 SG 干细胞分化外，我们还观察到，该途径还间接抑制毛囊间表皮表面的 SG。 PPARγ/K5 双阳性群体可能识别出产生腺体中分化的皮脂细胞。该提案旨在确定一些调节 SG 干细胞的复杂因素，以测试 SG 的作用正常皮肤功能，并确定PPARγ/K5双阳性群体是否表现出干细胞在目标 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，并测试表观原的上调是否在功能上与表皮中的 Notch 破坏相关在目标 3 中，我们将评估 SG 维持是否需要 PPARγ，以及是否需要 SG 扩展。表达该转录因子的细胞可以充当 SG 干细胞最后，我们将表征其定位。总之，这些研究将在正常和病理性人类皮肤中检测 PPARγ/K5 双阳性细胞。阐明 SG 干细胞如何在本地和远距离受到调节，同时有可能揭示新的 SG 功能在皮肤中的作用。