Dysregulation of BMP4 Signaling in FOP

描述(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环境中BMP4的浓度，也不能适当地调节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 I型受体(BMPRIA)存在于FOP细胞表面，并在高水平激活，而BMP Ib型受体(BMPRIB)存在于低水平。这些关于FOP细胞的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，而胚胎BMPRIB的低表达可导致数字畸形，与FOP患者的数字畸形非常相似。在FOP患者中，编码BMP4、多种BMP4拮抗剂、通路特异性或抑制性Smads或BMP受体的基因没有突变。综上所述，这些数据提示FOP细胞的BMP4信号通路可能存在初级缺陷，BMPRIA可能对FOP细胞的正常信号具有结构性的活性和/或无反应。我们假设FOP细胞中BMP信号的混杂(A)是细胞表面BMPRIA数量增加的结果，(B)介导FOP的病理生理。这项研究计划将重点研究与FOP细胞表面高稳定水平的BMPRIA蛋白相关的细胞信号事件。我们打算：(1)确定FOP细胞中BMPRIA过多激活的信号转导通路；(2)确定FOP细胞表面BMPRIA过多的机制；(3)确定FOP细胞中的BMPRIA信号是配体介导的还是配体独立的；以及(4)研究细胞表面BMPRIA过多是否足以介导“FOP表型”。在FOP中分析人类BMP4途径的分子病理学将促进阐明这种致残人类疾病中正常和无序骨诱导的基本机制的长期目标。这一策略还将导致一种更合理的治疗方法，用于治疗涉及人类成骨诱导的各种疾病。

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.