MPZL3 as a Therapeutically Targetable Mitochondrial Regulator of Sebaceous Gland Homeostasis and Sebum Production

项目摘要 除了对表皮屏障功能至关重要的皮脂的产生，皮肤弹性， 在体温调节和微生物组管理方面，皮脂腺(SG)也发挥着重要作用 免疫、代谢和(神经)内分泌功能。由于SG分化和皮脂的失调 产物见于许多皮肤病，如寻常痤疮、疤痕性脱发、脂溢性皮炎和 皮脂腺肿瘤：SG分化和皮脂的中心新分子对照的鉴定 生产将有助于为这些皮肤病的治疗干预确定新的目标。海流 翻译研究项目旨在确定髓鞘蛋白零样蛋白3(MPZL3)是一种新的治疗方法 通过控制皮脂细胞(SB)调控SG动态平衡和皮脂产生的靶向关键调控因子 小鼠皮肤和人皮肤中的增殖和脂肪生成。这个项目是基于我们的观察， 全球敲除(GKO)小鼠的MPZL3，一种表皮分化的重要线粒体调节因子，显示 皮脂分泌过多，持续的SG增生和SB过度增殖。这将是第一个 在SG/SB生物学背景下询问MPZL3的调节功能。基于表型相似性 在Mpzl3 GKO小鼠和KO小鼠之间对SG分化的关键转录调节因子PPARg进行了研究 MPZL3调控序列中假定的PPARg反应元件的存在和初步数据 显示PPARg激动剂治疗后Mpzl3表达上调，我们假设MPZL3发挥作用 紧接在PPARg下游，调节SB的增殖和分化。目标1将确定更改 在全球Mpzl3缺失的情况下，SG动态平衡和皮脂产生。定量(免疫)组织形态- Metry和qRT-PCR，以及基于LCM的RNAseq和通路分析将识别关键途径 在Mpz13 GKO皮肤上发生了变化。这些结果将与高级脂质组学和蛋白质组学分析相关联 用质谱仪鉴定SB分化过程中脂类通路中MPZL3依赖的变化。目标2 将区分上皮细胞和非上皮细胞，MPZL3依赖的信号通过以下方式调节SG功能 比较K14-Cre介导的皮肤上皮细胞特异性Mpz13-epKO小鼠和GKO小鼠的SG表型。 目的3确定MPZL3在人SBS中的功能以及PPARg对MPZL3功能的调节 使用体外(人SZ95 SBS)、体外(人皮肤器官培养)和新型人SG 3D有机化合物作为 以及体内模型(Mpz13 GKO和EPKO小鼠)。我们的研究将为控制艾滋病提供重要的见解。 小鼠和人类的SG生理学至少部分是通过MPZL3受线粒体调节的。我们希望 将MPZL3确定为与SG病理相关的皮肤病的创新、可用药靶点，并极大地 促进我们对MPZL3在哺乳动物皮肤生物学中进化保守功能的理解。

Project Summary Besides the production of sebum, which is essential for epidermal barrier function, skin elasticity, thermoregulation and microbiome management, the sebaceous gland (SG) also exerts important immunological, metabolic and (neuro)endocrine functions. Since dysregulated SG differentiation and sebum production are seen in many skin diseases such as acne vulgaris, scarring alopecia, seborrheic dermatitis and sebaceous tumors, the identification of central new molecular controls of SG differentiation and sebum production will help to pinpoint new targets for therapeutic intervention for these skin diseases. The current translational research project aims to identify myelin protein zero-like 3 (MPZL3) as a novel, therapeutically targetable key regulator of SG homeostasis and sebum production via the control of sebocyte (SB) proliferation and lipogenesis, in both murine and human skin. This project is based on our observation that global knockout (GKO) mice for MPZL3, an essential mitochondrial regulator of epidermal differentiation, show excessive sebum production, persistent SG hyperplasia and SB hyperproliferation. It will be the first to interrogate the regulatory function of MPZL3 in a SG/SB biology context. Based on phenotype similarities between Mpzl3 GKO mice and KO mice for PPARg, a key transcriptional regulator of SG differentiation, the presence of putative PPARg responsive elements in MPZL3 regulatory sequence, and preliminary data showing up-regulated Mpzl3 expression upon PPARg agonist treatment, we hypothesize that MPZL3 functions immediately downstream of PPARg to regulate SB proliferation and differentiation. Aim 1 will identify changes in SG homeostasis and sebum production upon global Mpzl3 deletion. Quantitative (immuno-)histomorpho- metry and qRT-PCR, along with LCM-based RNAseq and pathway analysis will identify critical pathways altered in Mpzl3 GKO skin. These results will be correlated with advanced lipidomics and proteomics analyses by mass spectrometry to identify MPZL3-dependent changes in lipid pathways during SB differentiation. Aim 2 will distinguish epithelia-derived from extra-epithelial, MPZL3-dependent signals that regulate SG function by comparing the SG phenotype in K14-Cre mediated, skin epithelia-specific Mpzl3 epiKO mice with GKO mice. Aim 3 will determine the function of MPZL3 in human SBs and the regulation of MPZL3 function by PPARg using in vitro (human SZ95 SBs), ex vivo (human skin organ culture) and novel human SG 3D organoids, as well as in vivo models (Mpzl3 GKO and epiKO mice). Our studies will provide critical insights into the control of murine and human SG physiology as being, at least in part, mitochondrially regulated via MPZL3. We expect to identify MPZL3 as an innovative, drugable target for skin diseases associated with SG pathology and greatly advance our understanding of the evolutionarily conserved functions of MPZL3 in mammalian skin biology.