PDGFRB Signaling in Progressive Skin Disease

项目摘要/摘要 解决罕见遗传病的发病机制有助于更好地理解基本生理和基因 功能。最近发现，编码血小板衍生的PDGFRb的功能获得突变 生长因子受体β(PDGFRβ)，出人意料地与涉及皮肤的综合征疾病有关。这个 表型包括类似于加速衰老的皮肤萎缩，或者矛盾的是，皮肤增厚和 纤维化并有瘢痕疙瘩样疤痕。这些观察结果提出了关于PDGFRβ功能的重要问题 皮肤，包括负责疾病的靶细胞类型和信号通路。不管是不同的人类 由于迄今患者数量有限，PDGFRb突变导致不同的疾病表型尚不清楚 以及缺乏合适的遗传模型。解决这些问题将使人们对PDGFRβ的作用有新的了解 在皮肤里。目的是确定PDGFRβ调节的控制真皮细胞的机制和它们的 对皮肤病和生理学的贡献。中心假设是真皮成纤维细胞中的PDGFRβ控制 下游效应器的平衡，包括STATS和AKT，这对维持健康至关重要 皮肤不平衡，疾病不平衡。AIM 1将在小鼠中使用可诱导的Cre/LOX方法来诱导PDGFRβ STAT家族成员联合缺失的成纤维细胞或真皮脂肪细胞中的激活突变 并统计靶基因，以发现新的真皮纤维化下游介质。目标2将描述一种新的 在小崎氏过度生长综合征小鼠模型中发现突变，并检验AKT激活的假说 对于皮肤脂肪组织进行性丧失的过度生长是必需的。《目标3》将描述一种新的鼠标 5-羟色胺孕激素综合征突变的模型，并检验STAT1是中枢调节因子的假设 突变型成纤维细胞的早孕皮肤表型和抗生长特性。这个项目借鉴了 PI在解决皮肤中PDGFRβ信号升高的矛盾后果方面的专业知识 疾病。该项目的结果将通过解剖细胞来开发两种人类疾病的遗传模型 PDGFRβ信号在真皮纤维化和真皮脂肪组织萎缩中的类型特异性作用，并通过建立 皮肤中PDGFRβ-STAT信号的概念框架。这一信息可能指向新的治疗方法 在这些罕见的遗传性疾病之外的背景下的纤维化和老龄化的战略。

Project Summary/Abstract Solving the pathogenesis of rare genetic diseases leads to greater understanding of basic physiology and gene function. It was recently discovered that gain-of-function mutations in human PDGFRB, encoding platelet-derived growth factor receptor β (PDGFRβ), unexpectedly associate with syndromic diseases involving the skin. The phenotypes involve dermal atrophy resembling accelerated aging or, paradoxically, dermal thickening and fibrosis with keloid-like scarring. These observations raise important questions about functions of PDGFRβ in the skin, including the target cell types and signaling pathways responsible for disease. Whether different human PDGFRB mutations cause distinct disease phenotypes is unclear because of limited numbers of patients to date and lack of appropriate genetic models. Addressing these questions will shed new light on the role of PDGFRβ in the skin. The objective is to identify PDGFRβ-regulated mechanisms controlling dermal cells and their contribution to skin disease and physiology. The central hypothesis is that PDGFRβ in dermal fibroblasts controls the balance of downstream effectors including STATs and AKT, which are critical for the maintenance of healthy skin and are imbalanced in disease. Aim 1 will use inducible Cre/lox approaches in mice to induce PDGFRβ activating mutations in fibroblasts or dermal adipocytes, with combinatorial deletion of STAT family members and STAT target genes to uncover new downstream mediators of dermal fibrosis. Aim 2 will characterize a new mouse model with a mutation found in Kosaki overgrowth syndrome, and test the hypothesis that AKT activation is required for overgrowth with progressive loss of dermal adipose tissue. Aim 3 will characterize a new mouse model with a Penttinen progeroid syndrome mutation, and test the hypothesis that STAT1 is a central mediator of the progeroid skin phenotype and anti-growth characteristics of mutant fibroblasts. This project draws on the PI’s expertise in PDGF signaling to resolve the paradoxical consequences of elevated PDGFRβ signaling in skin disease. The results of this project will develop genetic models of two human diseases, by dissecting the cell type-specific role of PDGFRβ signaling in dermal fibrosis and dermal adipose tissue atrophy, and by establishing the conceptual framework of PDGFRβ-STAT signaling in the skin. This information may point to novel therapeutic strategies for fibrosis and aging in contexts beyond these rare genetic diseases.