Dysregulation of BMP4 Signaling in FOP

FOP 中 BMP4 信号传导失调

• 批准号: 6945925
• 负责人: FREDERICK Samuel KAPLAN
• 金额: $ 34.87万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945925
• 关键词: RNA interference; athymic mouse; biological signal transduction; bone morphogenetic proteins; cell line; clinical research; enzyme activity; enzyme linked immunosorbent assay; genetic regulation; growth factor receptors; human genetic material tag; human subject; immunoprecipitation; mitogen activated protein kinase; molecular pathology; phosphorylation; progressive myositis ossificans; protein biosynthesis; protein degradation; protein protein interaction; receptor binding; receptor expression; serine threonine protein kinase; transcription factor

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.

描述（由申请人提供）：进行性骨化性纤维发育不良 (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常染色体显性致残性疾病。我们之前的研究表明，FOP 细胞无法正确调节 BMP4 的环境浓度，也无法正确调节 BMP 途径靶基因的转录，包括 BMP4 拮抗剂的转录。最近的初步数据表明，FOP 细胞表面存在高水平的 BMP IA 型受体 (BMPRIA) 且具有高活性，而 BMP IB 型受体 (BMPRIB) 则以低水平存在。 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 过度表达可导致异位骨化，而胚胎时期 BMPRIB 表达不足可导致数字畸形，与 FOP 患者所见的畸形非常相似。 FOP 患者中编码 BMP4、多种 BMP4 拮抗剂、途径特异性或抑制性 Smad 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 信号传导途径可能存在主要缺陷，并且 BMPRIA 可能对 FOP 细胞中的正常信号传导具有组成型活性和/或无反应。我们假设 FOP 细胞中混杂的 BMP 信号传导 (a) 是由于细胞表面 BMPRIA 数量增加造成的，(b) 介导了 FOP 的病理生理学。该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传导事件。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信号传导是配体介导的还是配体独立的； (4) 研究细胞表面过量的 BMPRIA 是否足以介导“FOP 表型”。对 FOP 中人类 BMP4 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。这一策略还将为涉及人类成骨诱导的多种疾病带来更合理的治疗方法。