The Cellular and molecular Basis of FOP Lesions

FOP 病变的细胞和分子基础

• 批准号: 8582260
• 负责人: FREDERICK Samuel KAPLAN
• 金额: $ 15.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582260
• 关键词: ACVR1 gene; Biological Assay; Biological Models; Biomechanics; Bone Morphogenetic Proteins; Bone Regeneration; Cell Differentiation process; Cell Fate Control; Cell Line; Cell Shape; Cell Surface Receptors; Cells; Cellular biology; Characteristics; Chondrogenesis; Clinical; Cues; Cytokine Signaling; Data; Development; Disease; Elasticity; Embryo; Environment; Fibroblasts; Foundations; Genes; Germ-Line Mutation; Growth Factor; Head; Hereditary Disease; Heterotopic Ossification; Interdisciplinary Study; Investigation; Knock-in Mouse; Knowledge; Lead; Lesion; Mechanics; Mediating; Medicine; Mesenchymal Stem Cells; Military Personnel; Modeling; Molecular; Molecular Biology; Mus; Mutation; Normal Cell; Osteogenesis; Pathway interactions; Patients; Physiological; Plague; Population; Rare Diseases; Receptor Mediated Signal Transduction; Research; Research Personnel; Series; Signal Pathway; Signal Transduction; Skeletal bone; Spinal Cord; Stem cells; Tissue Engineering; Tissues; War; Work; abstracting; base; bone; cartilage repair; chondro osseous differentiation; cytokine; effective therapy; experience; human disease; in vivo; innovation; insight; malformation; motor vehicle injury; mutant; programs; progressive myositis ossificans; public health relevance; receptor; response; skeletal; therapeutic target

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.

描述（由申请人提供）：FOP 祖细胞中机械转导的改变 摘要 罕见的遗传性疾病虽然直接影响相对较小的人群，但却是由基因突变引起的，其重要性如此之高，以至于其功能的变化很少被容忍，这提供了独特的见解进入基本的细胞机制。其中一种疾病是进行性骨化性纤维发育不良 (FOP)，它是由细胞命运决定控制失控引起的，导致先天性骨骼畸形和进行性致残的骨骼外（异位）软骨内骨化。我们确定所有家族性和散发性经典 FOP 病例均携带相同的 ACVR1/ALK2 杂合突变（R206H；c.617G>A），ACVR1/ALK2 是一种介导骨形态发生蛋白 (BMP) 信号转导的细胞表面受体。我们的数据表明，ACVR1 R206H 至少部分通过轻度激活 BMP 独立信号传导来激活 BMP 通路。祖细胞的定型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至特定的谱系，包括作为早期细胞的调节因子的 BMP。 发育和细胞分化。然而，细胞在体内存在于机械环境中，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（例如拉伸变形）。这些机械信号还可以指导细胞命运决定，并通过一些传递经典可溶性因子/细胞因子信号的相同途径介导。我们提出，R206H ACVR1 受体突变增强祖细胞对与细胞分化的分子和机械调节剂的相互作用更加敏感，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发作。我们假设 ACVR1 R206H 突变增强的 BMP 信号传导改变了间充质干细胞的正常细胞分化“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。一个新的多学科研究团队将共同致力于这项 BIRT 提案，以实现两个具体目标。目标 1：研究 Acvr1R206H 突变细胞对静态机械力和细胞微环境中改变的细胞力学的软骨形成反应。该目标将检查有和没有 Acvr1R206H 突变的细胞内部细胞收缩机制的差异，以及它们对生态位弹性（基质刚度）变化的反应。目标 2：研究 Acvr1R206H 突变细胞对细胞微环境主动机械力（细胞变形）的软骨形成反应。该目标将检查 ACVR1 R206H 突变与改变细胞形状（生态位的拉伸变形）的外部施加机械力的相互作用。拟议的高度创新的研究将由一个新的、协同的、多学科的、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。