PDGFRB Signaling in Progressive Skin Disease

进行性皮肤病中的 PDGFRB 信号传导

• 批准号: 10583948
• 负责人: LORIN E OLSON
• 金额: $ 54.72万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-08 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583948
• 关键词: AKT1 gene; Acceleration; Address; Adipocytes; Adipose tissue; Adult; Aging; Animal Genetics; Animal Model; Animals; Atrophic; Cell Aging; Cell Cycle; Cell physiology; Cells; Characteristics; Cicatrix; Complex; Connective Tissue; Data; Dermal; Dermis; Disease; Diving; Epidermis; Equilibrium; Exhibits; Family member; Fibroblasts; Fibrosis; Gene Deletion; Genes; Genetic; Genetic Epistasis; Genetic Models; Genotype; Growth; Hair; Health; Human; IGF1 gene; In Vitro; Insulin-Like Growth Factor I; Keloid; Lesion; Lipoatrophy; Maintenance; Mediating; Mediator; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; PDGFA gene; PDGFRB gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Pericytes; Phenotype; Phosphorylation; Physiological; Physiology; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Proto-Oncogene Proteins c-akt; Publications; Regenerative Medicine; Role; STAT1 gene; STAT1 protein; Sensory; Signal Pathway; Signal Transduction; Skin; Skin Physiology; Smooth Muscle Myocytes; Stat5 protein; Syndrome; Testing; Tissues; Vascular Smooth Muscle; aged; cell type; combinatorial; disease phenotype; experimental study; gain of function; gain of function mutation; gene function; genetic approach; genome sequencing; human disease; in vivo; inducible Cre; inhibitor; interest; mouse genetics; mouse model; mutant; novel therapeutic intervention; overexpression; permissiveness; platelet function; pup; rare genetic disorder; skin disorder; skin fibrosis; transcription factor; treatment strategy

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.

项目概要/摘要 解决罕见遗传病的发病机制可以加深对基础生理学和基因的了解 功能。最近发现人类 PDGFRB 的功能获得性突变，编码血小板衍生的 生长因子受体 β (PDGFRβ) 出乎意料地与涉及皮肤的综合征性疾病相关。这 表型涉及类似于加速衰老的真皮萎缩，或者矛盾的是，真皮增厚和 纤维化并伴有瘢痕疙瘩样疤痕。这些观察结果提出了关于 PDGFRβ 的功能的重要问题 皮肤，包括导致疾病的靶细胞类型和信号通路。无论是不同的人 由于迄今为止患者数量有限，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。解决这些问题将为 PDGFRβ 的作用提供新的线索 在皮肤中。目的是确定 PDGFRβ 调节机制，控制真皮细胞及其 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（包括 STAT 和 AKT）的平衡，这对于维持健康至关重要 皮肤和疾病的不平衡。目标 1 将在小鼠中使用诱导型 Cre/lox 方法诱导 PDGFRβ 激活成纤维细胞或真皮脂肪细胞的突变，并组合删除 STAT 家族成员 和 STAT 靶基因以发现真皮纤维化的新下游介质。目标 2 将描述一个新的 具有 Kosaki 过度生长综合征突变的小鼠模型，并测试 AKT 激活的假设 是过度生长和真皮脂肪组织逐渐丧失所必需的。 Aim 3 将描述一款新鼠标的特征 具有 Penttinen 早衰综合征突变的模型，并检验 STAT1 是中心介质的假设 早衰皮肤表型和突变成纤维细胞的抗生长特征。该项目借鉴了 PI 在 PDGF 信号传导方面的专业知识可解决皮肤中 PDGFRβ 信号传导升高的矛盾后果 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 信号传导的概念框架。该信息可能指向新的治疗方法 这些罕见遗传疾病之外的纤维化和衰老策略。