Dysregulation of BMP4 Signaling in FOP

描述（由申请人提供）：进行性骨化纤维发育不良（FOP）患者的细胞中BMP4信号通路失调，FOP是一种进行性异位骨化和先天性肢体畸形的致残性常染色体显性遗传病。我们之前的研究表明，FOP细胞不能适当调节环境中BMP4的浓度，也不能适当调节BMP通路靶基因的转录，包括BMP4拮抗剂的转录。最近的初步数据表明，BMP IA型受体（BMPRIA）在FOP细胞表面高水平存在并活跃，而BMP IB型受体（BMPRIB）则低水平存在。FOP细胞的这些数据与发育研究一致，这些研究表明，出生后BMPRIA的过表达可导致异位骨化，而胚胎BMPRIB的过表达可导致数字畸形，与FOP患者的情况非常相似。在FOP患者中，编码BMP4、多种BMP4拮抗剂、途径特异性或抑制性Smads或BMP受体的基因没有突变。综上所述，这些数据表明FOP细胞中的BMP4信号通路可能存在原发性缺陷，并且BMPRIA可能对FOP细胞中的正常信号通路具有组成性活性和/或无反应。我们假设FOP细胞中混杂的BMP信号(a)是由细胞表面BMPRIA数量增加引起的，(b)介导了FOP的病理生理。本研究计划将重点研究与FOP细胞表面高稳态水平BMPRIA蛋白相关的细胞信号事件。我们打算：(1)表征FOP细胞中过量BMPRIA激活的信号转导途径；(2)确定导致FOP细胞表面BMPRIA过量的机制；(3)确定FOP细胞中的BMPRIA信号是配体介导的还是与配体无关的；(4)研究细胞表面过量的BMPRIA是否足以介导“FOP表型”。分析人类BMP4通路在FOP中的分子病理学将有助于阐明这种致残人类疾病正常和紊乱骨诱导的基本机制。这一策略也将导致一种更合理的治疗方法，以治疗涉及诱导人类成骨的各种疾病。

DESCRIPTION (provided by applicant): The BMP4 signaling pathway is dysregulated in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a disabling autosomal dominant disorder of progressive heterotopic ossification and congenital limb malformations. Our previous studies suggest that FOP cells fail to properly regulate ambient concentrations of BMP4 and fail to appropriately regulate the transcription of BMP pathway target genes, including those for the BMP4 antagonists. Recent preliminary data indicate that the BMP type IA receptor (BMPRIA) is present and active at high levels on the surface of FOP cells, while the BMP type IB receptor (BMPRIB) is present at low levels. These data for FOP cells are consistent with developmental studies, which show that postnatal over-expression of BMPRIA can cause heterotopic ossification and that embryonic underexpression of BMPRIB can lead to digital malformations that closely mimic those seen in patients who have FOP. There are no mutations in the genes encoding BMP4, multiple BMP4 antagonists, pathway-specific or inhibitory Smads, or the BMP receptors in FOP patients. Taken together, these data suggest that a primary defect may exist in the BMP4 signaling pathway in FOP ceils and that BMPRIA may be constitutively active and/or unresponsive to normal signaling in FOP cells. We hypothesize that promiscuous BMP signaling in FOP cells (a) results from increased amounts of BMPRIA on the cell surface, and (b) mediates the pathophysiology of FOP. This research proposal will focus on investigations of cellular signaling events that are associated with the high steady-state levels of BMPRIA protein on the surface of FOP cells. We intend to: (1) characterize the signal transduction pathways that are activated by overabundant BMPRIA in FOP cells; (2) determine the mechanism leading to BMPRIA overabundance on the surface of FOP cells; (3) establish whether BMPRIA signaling in FOP cells is ligand-mediated or ligand independent; and (4) investigate whether over-abundance of BMPRIA on the cell surface is sufficient to mediate an "FOP phenotype". Analysis of the molecular pathology of the human BMP4 pathway in FOP will foster the long-term goal of elucidating basic mechanisms of normal and disordered bone induction in this disabling human disease. This strategy will also lead to a more rational therapeutic approach to a wide variety of disorders involving the induction of osteogenesis in humans.