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.

项目总结/摘要 解决罕见遗传病的发病机制导致对基本生理学和基因的更好理解 功能最近发现，人PDGFRB中的功能获得性突变，其编码血小板源性 生长因子受体β（PDGFRβ），意外地与涉及皮肤的综合征性疾病相关。的 表型涉及类似于加速老化的皮肤萎缩，或者矛盾的是，皮肤增厚， 纤维化伴瘢痕疙瘩样疤痕这些观察结果提出了有关PDGFRβ功能的重要问题， 皮肤，包括靶细胞类型和负责疾病的信号通路。是否不同的人类 PDGFRB突变导致不同的疾病表型尚不清楚，因为迄今为止患者数量有限 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 在皮肤上。目的是确定PDGFRβ调节机制，控制真皮细胞及其功能。 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控制了 包括STAT和AKT在内的下游效应物的平衡，这对于维持健康至关重要 皮肤和不平衡的疾病。目的1利用诱导型Cre/lox方法在小鼠体内诱导PDGFRβ 成纤维细胞或真皮脂肪细胞中的激活突变，伴有STAT家族成员的组合缺失 和STAT靶向基因，以发现真皮纤维化的新下游介质。目标2将描述一个新的 在Kosaki过度生长综合征中发现突变的小鼠模型，并测试AKT激活 是皮肤脂肪组织逐渐减少的过度生长所必需的。目标3将描述一种新的小鼠 模型与Penttinen progeroid综合征突变，并测试假设，STAT 1是一个中央调解人 的早衰症皮肤表型和突变成纤维细胞的抗生长特性。该项目借鉴了 PI在PDGF信号传导方面的专业知识，以解决皮肤中PDGFRβ信号传导升高的矛盾后果 疾病该项目的成果将通过解剖细胞， 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， 皮肤中PDGFRβ-STAT信号传导的概念框架。这些信息可能指向新的治疗方法， 在这些罕见的遗传疾病之外的环境中为纤维化和衰老制定策略。