The Cellular and molecular Basis of FOP Lesions

罕见的遗传性疾病，虽然直接影响相对较小的人群，但是由基因突变引起的，这些基因突变非常重要，以至于它们的功能变化很少被容忍，这为基本的细胞机制提供了独特的见解。进行性骨化纤维发育不良（FOP）就是这样一种疾病，它是由细胞命运决定的错误控制引起的，导致先天性骨骼畸形和进行性致残性骨外（异位）软骨内成骨。我们确定所有家族性和散发性经典FOP病例携带相同的ACVR1/ALK2 （R206H; c.617G>A）杂合突变，ACVR1/ALK2是一种介导骨形态发生蛋白（BMPs）信号转导的细胞表面受体。我们的数据表明，ACVR1 R206H至少在一定程度上通过轻度激活BMP非依赖性信号通路来激活BMP通路。祖细胞的承托和分化受到来自组织微环境的信号的调节，这些信号将细胞命运引导到特定的谱系，包括早期建立的调节因子bmp

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.