Dysregulation of BMP4 Signaling in FOP

描述（由申请方提供）：在进行性骨化性纤维发育不良（FOP）患者的细胞中，BMP 4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疾病。我们以前的研究表明，FOP细胞不能适当地调节BMP 4的环境浓度，也不能适当地调节BMP途径靶基因的转录，包括BMP 4拮抗剂的转录。最近的初步数据表明，BMP IA型受体（BMPRIA）在FOP细胞表面上以高水平存在并具有活性，而BMP IB型受体（BMPRIB）以低水平存在。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的过度表达可导致异位骨化，而BMPRIB的胚胎低表达可导致与FOP患者中所见非常相似的指畸形。FOP患者中编码BMP 4、多种BMP 4拮抗剂、通路特异性或抑制性Smads或BMP受体的基因没有突变。总之，这些数据表明，FOP细胞中的BMP 4信号传导途径中可能存在原发性缺陷，并且BMPRIA可能是组成型活性的和/或对FOP细胞中的正常信号传导无反应。我们假设FOP细胞中混杂的BMP信号传导（a）由细胞表面上BMPRIA的量增加引起，并且（B）介导FOP的病理生理学。这项研究计划将集中在与FOP细胞表面高稳态水平的BMPRIA蛋白相关的细胞信号事件的调查。我们打算：（1）表征由FOP细胞中过量BMPRIA激活的信号转导途径;（2）确定导致FOP细胞表面上BMPRIA过量的机制;（3）确定FOP细胞中BMPRIA信号传导是配体介导的还是配体非依赖性的;和（4）研究细胞表面上过量BMPRIA是否足以介导“FOP表型”。对FOP中人BMP 4通路的分子病理学分析将促进阐明这种致残性人类疾病中正常和紊乱骨诱导的基本机制的长期目标。这一策略也将导致一个更合理的治疗方法，以各种各样的疾病，涉及诱导成骨在人类。

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.