Novel Zebrafish Models for Human Fibrodysplasia Ossificans Progressiva

项目摘要/摘要 颅面和骨骼的发育和动态平衡是一个复杂的相互作用的顶峰 令人惊讶的巨大且数量不断增加的组织，血液和血管系统中的成分，免疫 反应和生长因子信号转导。尽管对复杂的信号通路的了解导致 人类矿化组织疾病在过去几十年里有所改善，详细了解了 大多数人类矿化组织疾病仍然难以捉摸。 在这里，我们建议使用新创建的表达构成活性(CA)的转基因斑马鱼品系。 Alk8/ACVR1基因作为进展性骨纤维发育不良(FOP)模型的研究FOP是一种致命的疾病 特点是随着时间的推移，软组织的进行性异位骨化(HO)最终导致 死亡年龄约40岁。 拟议研究的目标是：1)建立斑马鱼FOP模型；2)确定祖细胞 3)利用FOP斑马鱼识别小分子 FOP的抑制剂。我们的方法包括新创建的转基因斑马鱼品系，表达结构性活性 (CA)Alk8/ACVR1作为人类进展性骨纤维发育不良(FOP)模型。转基因途径 将用于标记和谱系追踪与人类FOP有关的四种细胞类型，小分子筛查将 被询问以确定激活Alk8/ACVR1突变的抑制物。 我们发表的斑马鱼矿化组织发育和分子遗传学特征方面的专业知识 疾病，强大的初步数据，以及临床、发育和免疫学研究团队支持 我们实现所提出目标的能力。我们预期拟议的研究完成后， 结果显著提高了对FOP分子基础的了解，这将促进 预防和/或治愈这种衰弱的矿化组织疾病的有效靶向疗法。在……里面 此外，阐明引导HO的分子信号也可以用来设计更有效的策略 以有控制和定向的方式再生骨骼。 拟议研究的意义和与公共卫生的相关性包括以下事实：骨骼和 仅在美国，每700名活产儿中就有1人出现头面部缺陷，这使得这是一个严重的 健康问题。此外，在其他人类疾病中也观察到HO，如钙化性心脏瓣膜疾病和 动脉粥样硬化，使这些研究对许多与衰老相关的疾病具有潜在的益处 人口。

Project Summary/Abstract Craniofacial and skeletal development and homeostasis is the culmination of a complex interplay between a surprisingly large and growing number of tissues, components in the blood and vasculature, the immune response and growth factor signaling. Although knowledge of the complex signaling pathways resulting in human mineralized tissue diseases has improved over the past few decades, a detailed understanding of the majority of human mineralized tissue diseases remains elusive. Here we propose to use newly created transgenic zebrafish lines expressing constitutively active (CA) Alk8/ACVR1 genes as models for human Fibrodysplasia Ossificans Progressiva (FOP). FOP is a fatal disease characterized by the progressive heterotopic ossification (HO) of soft tissues over time eventually resulting in death at age ~40 years. The objectives of the proposed studies are to: 1) establish zebrafish models for FOP; 2) identify the progenitor cells that ultimately contribute to HO in humans with FOP; and 3) exploit FOP zebrafish to identify small molecule inhibitors of FOP. Our methods include newly created transgenic zebrafish lines expressing constitutively active (CA) Alk8/ACVR1 as models for human Fibrodysplasia Ossificans Progressiva (FOP). Transgenesis approaches will be used to label and lineage trace four cell types implicated in human FOP, and small molecule screens will be interrogated to identify inhibitors of activating Alk8/ACVR1 mutations. Our published expertise in molecular genetic characterizations of zebrafish mineralized tissue development and disease, strong preliminary data, and team of clinical, developmental, and immunological investigators supports our ability to accomplish the proposed Aims. We anticipate that the completion of the proposed studies will result in significantly improved knowledge of the molecular basis of FOP, which will facilitate the generation of effective targeted therapies for the prevention and/or cure of this debilitating mineralized tissue disease. In addition, elucidation of the molecular signals directing HO may also be used to devise more effective strategies to regenerate bone in a controlled and directed manner. The significance of the proposed studies and relevance to public health includes the fact that skeletal and craniofacial defects occur in as many as 1 in 700 live births in the United States alone, making this a serious health issue. In addition, HO is observed in other human diseases such as calcific heart valve disease and atherosclerosis, making these studies of potential benefit for numerous diseases associated with the aging populations.