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

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 骨外骨骼称为异位骨化(HO)。HO由一系列细胞和组织引起- 导致骨骼肌和其他软结缔组织内骨形成的广泛事件。都是家族成员 具有典型FOP临床表现的散发性病例携带功能获得杂合性突变 在ACVR1(R206H；C.617G&gt；A)中，介导骨形态发生蛋白(BMP)的细胞表面受体 信号，这已经被认为是其软骨和成骨诱导潜力。异位骨 在FOP患者中形成的骨本质上是正常的软骨内骨，然而这种骨形成的启动 是受影响组织内错误的细胞命运决定的结果。HO可以自发形成 在肌肉或其他软结缔组织受伤后。除了配体-受体信号外， 来自物理环境的机械信号也直接决定细胞的命运，具有坚硬的底物。 促进软骨和成骨的命运和更柔软的底物促进神经性、成脂性和 肌源性细胞的命运。我们观察到在祖细胞中细胞机械转导的激活增加。 携带FOP突变。 该建议旨在确定Acvr1R206H突变导致的BMP信号升高对 细胞机械信号转导(也称为机械转导)及其如何影响 肌肉干细胞(MuSCs)用于损伤后再生骨骼肌。我会先确定是否提升了 Acvr1R206H细胞中的BMP信号与机械信号通路相互作用改变对底物的反应 僵硬导致间充质干细胞(MSCs)决定异常的细胞命运(目标1)。我也会 Acvr1R206H突变对肌肉组织细胞群肌肉干细胞能力的影响 细胞(MuSCs)，修复受损的骨骼肌组织(目标2)。虽然FOP是一种罕见的遗传病，但Ho是一种 对严重组织创伤的常见病理反应，如冲击波引发的损伤和关节 替代手术。从基因的角度更好地理解HO可以提供 洞察骨形成的异常调控机制并为药物提供靶点 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机械转导及其在肌肉再生中的作用 受伤后。

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.