The Cellular and molecular Basis of FOP Lesions

描述(申请人提供)：FOP祖细胞中机械转导的改变尽管直接影响人群中相对较小的部分，但罕见的遗传疾病是由非常重要的基因突变引起的，以至于很少容忍其功能的变化，这为基本的细胞机制提供了独特的见解。进行性纤维发育不良骨化症(FOP)就是这样一种疾病，其原因是对细胞命运的错误控制，导致先天性骨骼畸形和进行性致残性骨外(异位)软骨内骨化。我们确定，所有家族性和散发性的经典型FOP病例都携带ACVR1/ALK2(R206H；C.617G&gt；A)的杂合突变，ACVR1/ALK2是一种细胞表面受体，介导骨形态发生蛋白(BMPs)的信号转导。我们的数据表明，ACVR1R206H至少部分地通过温和地激活BMP非依赖信号来激活BMP途径。祖细胞的承诺和分化受到来自组织微环境的信号的调节，这些信号将细胞的命运引导到特定的谱系，包括作为早期调控因子的骨形成蛋白。 发育和细胞分化。然而，细胞存在于体内的机械环境中，通过生理活动经历不同弹性/刚度的局部微环境和动态机械信号(如拉伸变形)。这些机械信号也可以指导细胞命运的决定，并通过一些相同的途径来传递经典的可溶性因子/细胞因子的信号。我们认为，R206H ACVR1受体突变增强了祖细胞对与细胞分化的分子和机械调节器的相互作用的反应，并且在患者中，这种增强的敏感性可以触发和/或介导软骨内骨形成的活跃事件。我们推测，ACVR1R206H突变增强的BMP信号改变了间充质干细胞正常的细胞分化“设定点”，增加了这些细胞对 调节细胞命运决定的微环境机械线索。一个新的多学科调查团队将就BIRT提案共同努力，以实现两个具体目标。目的：研究Acvr1R206H突变细胞在细胞微环境中对静力和细胞力学改变的软骨形成反应。这一目标将检测具有和不具有Acvr1R206H突变的细胞的内部细胞收缩机制的差异，以及它们对生态位弹性(底物刚性)变化的反应。目的：研究Acvr1R206H突变细胞对细胞微环境中主动机械力(细胞变形)的软骨形成反应。这一目标将研究ACVR1R206H突变与改变细胞形状的外部机械力(壁龛的拉伸变形)的相互作用。拟议的高度创新的调查将由一个新的、协同的、多学科的和互动的研究小组进行，以确定控制细胞分化的调控机制，并提供基础 建立一个新的、创新的多学科研究计划。

DESCRIPTION (provided by applicant): Altered Mechanotransduction in FOP Progenitor Cells Abstract Rare genetic disorders, although directly impacting relatively small segments of the population, are caused by mutations in genes with such critical importance that changes in their functions are rarely tolerated, providing unique insight into fundamental cellular mechanisms. One such disease, fibrodysplasia ossificans progressiva (FOP) is caused by misregulated control of cell fate decisions that lead to congenital skeletal malformations and progressive disabling extra-skeletal (heterotopic) endochondral ossification. We determined that all familial and sporadic cases of classic FOP carry the same heterozygous mutation in ACVR1/ALK2 (R206H; c.617G>A), a cell surface receptor that mediates signal transduction of bone morphogenetic proteins (BMPs). Our data show that ACVR1 R206H activates the BMP pathway, at least in part, through mildly activating BMP- independent signaling. Commitment and differentiation of progenitor cells are regulated by signals from the tissue microenvironment that direct cell fate to specific lineages, including BMPs that are established regulators of early development and cell differentiation. However, cells exist in vivo in a mechanical environment, experiencing local microenvironments of varying elasticity/stiffness and dynamic mechanical signals (such as tensile deformation) through physiologic activities. These mechanical signals can also direct cell fate decisions, and are mediated through some of the same pathways that transmit signals from classical soluble factors/cytokines. We propose that the R206H ACVR1 receptor mutation enhances progenitor cells to be more responsive to interactions with molecular and mechanical modulators of cell differentiation, and that in patients this enhanced sensitivity can trigger and/or mediate active episodes of endochondral bone formation. We hypothesize that enhanced BMP signaling by the ACVR1 R206H mutation alters the normal cell differentiation "set-point" of mesenchymal stem cells, increasing the sensitivity of these cells to microenvironmental mechanical cues that modulate cell fate decisions. A new multi-disciplinary team of investigators will work together on this BIRT proposal to accomplish two specific aims. Aim 1: To investigate the chondrogenic response of Acvr1R206H mutant cells to static mechanical forces and altered cell mechanics in the cell microenvironment. This Aim will examine differences in the internal cellular contractile machinery in cells with and without the Acvr1R206H mutation, and their response to changes in the elasticity (substrate stiffness) of the niche. Aim 2: To investigate the chondrogenic response of Acvr1R206H mutant cells to active mechanical forces (cell deformation) from the cell microenvironment. This Aim will examine the interactions of the ACVR1 R206H mutation with externally applied mechanical forces that alter cell shape (tensile deformation of the niche). The proposed highly innovative investigations will be conducted by a new and synergistic, multi- disciplinary, and interactive research team in order to identify regulatory mechanisms controlling cell differentiation and provide the foundation for establishing a new and innovative multidisciplinary research program.