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

项目摘要 除了产生对表皮屏障功能、皮肤弹性至关重要的皮脂外， 除了体温调节和微生物组管理外，皮脂腺（SG）也发挥重要作用， 免疫、代谢和（神经）内分泌功能。由于SG分化和皮脂分泌失调， 在许多皮肤病中都可以看到这种物质的产生，例如寻常痤疮、疤痕性脱发、脂溢性皮炎和 皮脂腺肿瘤，SG分化和皮脂的中央新分子控制的鉴定 生产将有助于确定这些皮肤病治疗干预的新目标。当前 翻译研究项目的目的是确定髓鞘蛋白零样3（MPZL 3）作为一种新的，治疗 通过控制皮脂细胞（SB）实现SG体内平衡和皮脂产生的靶向关键调节剂 增殖和脂肪生成。这个项目是基于我们的观察， MPZL3（一种表皮分化的重要线粒体调节因子）的全基因敲除（GKO）小鼠显示， 过度的皮脂产生、持续的SG增生和SB过度增生。将率先 在SG/SB生物学背景下询问MPZL 3的调节功能。基于表型相似性 Mpzl3 GKO小鼠和KO小鼠之间的PPARg（SG分化的关键转录调节因子）， MPZL 3调控序列中存在假定的PPARg应答元件，以及初步数据 显示在PPARg激动剂处理后Mpzl3表达上调，我们假设MPZL3功能 紧邻PPARg下游以调节SB增殖和分化。目标1将确定变化 在SG体内平衡和皮脂产生中的作用。定量（免疫）组织形态 方法和qRT-PCR，沿着基于LCM的RNAseq和途径分析将确定关键途径 在Mpzl3 GKO皮肤中改变。这些结果将与先进的脂质组学和蛋白质组学分析相关联 通过质谱鉴定SB分化过程中脂质途径中MPZL 3依赖性的变化。目的2 将区分上皮来源的上皮外，MPZL 3依赖性信号，调节SG功能， 比较K14-Cre介导的皮肤上皮特异性Mpzl3 epiKO小鼠与GKO小鼠中的SG表型。 目的3：探讨MPZL 3在人SB中的功能及PPARg对MPZL 3功能的调节作用 使用体外（人SZ 95 SB）、离体（人皮肤器官培养物）和新型人SG 3D类器官， 以及体内模型（Mpz13 GKO和epiKO小鼠）。我们的研究将为控制 鼠和人SG生理学至少部分地通过MPZL 3进行神经调节。我们期望 将MPZL 3鉴定为与SG病理学相关的皮肤疾病的创新的、可药用的靶标， 推进我们对MPZL 3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.