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）：BMP4信号通路在患有纤维肿瘤发育异常的患者细胞中失调（FOP），这是一种残疾的渐进性异位骨化骨化和先红色肢体畸形的常染色体显性疾病。我们先前的研究表明，FOP细胞无法正确调节BMP4的环境浓度，并且无法适当调节BMP途径靶基因的转录，包括BMP4拮抗剂。最近的初步数据表明，BMP IA型受体（BMPRIA）存在，并且在FOP细胞表面高水平上活跃，而BMP IB受体（BMPRIB）的表面较低。这些针对FOP细胞的数据与发育研究一致，这些数据表明，BMPRIA的产后过表达可能引起异位骨化，并且BMPRIB的胚胎不足会导致数字畸形，这些数字畸形紧密模仿患者中有FOP的患者。编码BMP4，多个BMP4拮抗剂，途径特异性或抑制性SMAD或FOP患者中的BMP受体的基因中没有突变。综上所述，这些数据表明，在FOP CEIL中的BMP4信号通路中可能存在主要缺陷，并且BMPRIA可能具有组成性活性和/或对FOP细胞中正常信号的反应。我们假设FOP细胞中的混杂BMP信号传导（a）是由于细胞表面上的BMPRIA量增加而导致的，并且（b）介导了FOP的病理生理学。该研究建议将重点介绍与FOP细胞表面上与稳态水平高的BMPRIA蛋白相关的细胞信号事件的研究。我们打算：（1）表征FOP细胞中过多的BMPRIA激活的信号转导途径； （2）确定导致BMPRIA过度浮力在FOP细胞表面的机制； （3）确定FOP细胞中的BMPRIA信号传导是配体介导的还是与配体无关的； （4）研究BMPRIA在细胞表面上是否足以介导“ FOP表型”。对FOP中人类BMP4途径的分子病理的分析将促进这种残疾的人类疾病中正常和无序骨诱导基本机制的长期目标。该策略还将导致更合理的治疗方法，以涉及涉及人类成骨的多种疾病。