Intersection of Upregulated BMP Signaling & Cellular Mechanotransduction in fibrodysplasia ossificans progressiva (FOP)

上调 BMP 信号转导的交叉点

• 批准号: 9257232
• 负责人: Alexandra Katherine Stanley
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257232
• 关键词: ACVR1 gene; Abnormal Cell; Actins; Affect; Alpha Cell; Area; Atomic Force Microscopy; Biomechanics; Blast Cell; Bone Morphogenetic Proteins; Cartilage; Cell Differentiation process; Cell Lineage; Cell Surface Receptors; Cell model; Cell surface; Cells; Cellular Mechanotransduction; Cellular Morphology; Chondrogenesis; Chromatin; Clinical; Connective and Soft Tissue; Cues; Data; Embryo; Environment; Event; Fibroblasts; Genetic; Hereditary Disease; Heterotopic Ossification; Impairment; Injury; Intervention; Lead; Ligands; Measurement; Mechanics; Mechanoreceptors; Mediating; Mesenchymal; Mesenchymal Stem Cells; Morphology; Mus; Muscle; Muscle satellite cell; Mutation; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Pathologic; Pathway interactions; Patients; Perception; Pharmacologic Substance; Physical environment; Play; Population; Process; Proliferating; Receptor Signaling; Replacement Arthroplasty; Research; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Stress Fibers; Therapeutic; Tissues; Transplantation; bone; bone cell; cartilage cell; experimental study; gain of function; gain of function mutation; gene induction; in vivo; injured; insight; lipid biosynthesis; mechanotransduction; mouse model; muscle regeneration; myogenesis; non-genetic; osteogenic; progenitor; progressive myositis ossificans; receptor; receptor function; repaired; response; response to injury; rho; rhoA GTP-Binding Protein; soft tissue; stem cells; therapeutic target; tissue regeneration; tissue trauma; wound healing

Project Summary Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by the formation of extra-skeletal bone known as heterotopic ossification (HO). HO is caused by a series of cellular and tissue- wide events that lead to bone formation within skeletal muscle and other soft connective tissues. All familial and sporadic cases with a classic clinical presentation of FOP carry a gain-of-function heterozygous mutation in ACVR1 (R206H; c.617G>A), a cell surface receptor that mediates bone morphogenetic protein (BMP) signaling, which has been recognized for its chondro- and osteogenic-induction potential. The heterotopic bone that forms in FOP patients is qualitatively normal endochondral bone, however initiation of this bone formation occurs as a result of misdirected cell fate decisions within the affected tissue. HO can form both spontaneously and after injury to the muscle or other soft connective tissue. In addition to ligand-receptor signaling, mechanical cues derived from the physical environment also direct cell fate decisions, with stiff substrates promoting chondrogenic and osteogenic fates and softer substrates promoting neurogenic, adipogenic, and myogenic cell fates. We have observed increased activation of cellular mechanotransduction in progenitor cells harboring the FOP mutation. This proposal seeks to identify the influence of elevated BMP signaling conferred by the Acvr1R206H mutation on cellular mechanical signal transduction (also known as mechanotransduction) and how it affects the ability of muscle stem cells (MuSCs) to regenerate skeletal muscle after injury. I will first determine whether elevated BMP signaling in Acvr1R206H cells interacts with mechanical signaling pathways to alter response to substrate stiffness leading to aberrant cell fate decisions by mesenchymal stem cells (MSCs) (Aim 1). I will also investigate the effect of the Acvr1R206H mutation on the ability of a muscle tissue cell population, muscle stem cells (MuSCs), to repair damaged skeletal muscle tissue (Aim 2). While FOP is a rare genetic disease, HO is a common pathological response to severe tissue trauma scenarios such as blast-initiated injuries and joint- replacement surgeries. Developing a better understanding of HO from a genetic perspective could provide insight into the aberrant mechanisms regulating bone formation and provide targets for pharmaceutical intervention in both genetic and non-genetic causes of HO. Additionally, insights gained from this study will provide us with a better understanding of cellular mechanotransduction and its role in muscle regeneration after injury.

项目摘要 进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其特征是形成 称为异位骨化（HO）的骨骼外骨。HO是由一系列细胞和组织引起的- 导致骨骼肌和其他软结缔组织内骨形成的广泛事件。所有家族 具有典型FOP临床表现的散发病例携带功能获得性杂合突变 在ACVR 1（R206 H; c.617G>A）中，一种介导骨形态发生蛋白（BMP）的细胞表面受体 信号传导，其已被公认为具有软骨和成骨诱导潜力。异位骨 在FOP患者中形成的是定性上正常的软骨内骨，然而这种骨形成的起始 由于受影响组织内错误的细胞命运决定而发生。HO可以自发形成 以及在肌肉或其它软结缔组织损伤之后。除了配体-受体信号传导， 来自物理环境的机械线索也直接决定细胞的命运， 促进软骨形成和成骨命运，以及促进神经形成、脂肪形成和 肌原细胞命运我们已经观察到祖细胞中细胞力学转导的激活增加 携带FOP突变 该建议旨在鉴定由Acvr 1 R206 H突变赋予的升高的BMP信号传导对 细胞机械信号转导（也称为机械转导）以及它如何影响细胞的能力。 肌肉干细胞（MuSC）在损伤后再生骨骼肌。我将首先确定是否升高 Acvr 1 R206 H细胞中的BMP信号传导与机械信号传导途径相互作用以改变对底物的反应 僵硬导致间充质干细胞（MSC）的异常细胞命运决定（目的1）。我也会 研究Acvr 1 R206 H突变对肌肉组织细胞群，肌干细胞， 细胞（MuSC），以修复受损的骨骼肌组织（目的2）。虽然FOP是一种罕见的遗传性疾病，但HO是一种 对严重组织创伤情况的常见病理反应，如爆炸引发的损伤和关节损伤， 替代手术从遗传学的角度更好地理解HO可以提供 深入了解调节骨形成的异常机制，并为药物治疗提供靶点。 对HO的遗传和非遗传原因进行干预。此外，从这项研究中获得的见解将 使我们更好地了解细胞力学传导及其在肌肉再生中的作用 伤后