Novel Zebrafish Models for Human Fibrodysplasia Ossificans Progressiva

人类进行性骨化纤维发育不良的新型斑马鱼模型

• 批准号: 9369566
• 负责人: PAMELA C YELICK
• 金额: $ 21.78万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9369566
• 关键词: ACVR1 gene; Address; Age; Aging; Animal Model; Applications Grants; Atherosclerosis; Blood; Calcified; Cells; Cessation of life; Clinical; Complex; Connective and Soft Tissue; Craniofacial Abnormalities; Data; Defect; Degenerative polyarthritis; Development; Disease; Disease Progression; Etiology; Exhibits; Gene Targeting; Gene Transfer Techniques; Generations; Genetic; Goals; Grant; Growth Factor; Health; Heart Valve Diseases; Heat-Shock Response; Heterotopic Ossification; Homeostasis; Human; Immune; Immune response; Immunologics; Individual; Knowledge; Label; Live Birth; Methods; Minerals; Mission; Modeling; Molecular; Molecular Genetics; Molecular Target; Muscle; Mutagenesis; Mutation; Natural regeneration; Pharmacotherapy; Phenotype; Population; Prevention therapy; Public Health; Publishing; Recombinants; Reporter; Reproducibility; Research; Research Personnel; Signal Pathway; Signal Transduction; Skeletal Development; Stem cells; Techniques; Time; Tissues; Transgenic Organisms; United States; United States National Institutes of Health; Vascular Endothelial Cell; Zebrafish; age related; aging population; base; bone; calcification; cell type; craniofacial development; craniofacial repair; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; mineralization; new therapeutic target; novel; novel therapeutics; osteochondral tissue; prevent; progressive myositis ossificans; screening; skeletal; small molecule; small molecule inhibitor; soft tissue; targeted treatment

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.

项目概要/摘要 颅面和骨骼的发育和体内平衡是多种因素之间复杂相互作用的结果。 血液和脉管系统中的组织、成分、免疫系统的数量惊人地大且数量不断增加 反应和生长因子信号传导。尽管对复杂信号通路的了解导致 人类矿化组织疾病在过去的几十年里得到了改善，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组成型活性（CA）的转基因斑马鱼系 Alk8/ACVR1 基因作为人类进行性骨化性纤维发育不良 (FOP) 的模型。 FOP是一种致命疾病 其特点是软组织随着时间的推移逐渐异位骨化（HO），最终导致 死亡时约 40 岁。 拟议研究的目标是：1）建立 FOP 斑马鱼模型； 2）确定祖先 FOP 患者中最终产生 H2O 的细胞； 3）利用FOP斑马鱼识别小分子 FOP抑制剂。我们的方法包括新创建的表达组成型活性的转基因斑马鱼系 (CA) Alk8/ACVR1 作为人类进行性骨化性纤维发育不良 (FOP) 模型。转基因方法 将用于标记和谱系追踪与人类 FOP 相关的四种细胞类型，小分子筛选将 被询问以确定激活 Alk8/ACVR1 突变的抑制剂。 我们发表的斑马鱼矿化组织发育和分子遗传特征方面的专业知识 疾病、强有力的初步数据以及临床、发育和免疫学研究人员团队的支持 我们实现拟议目标的能力。我们预计拟议研究的完成将 显着提高了对 FOP 分子基础的了解，这将有助于生成 用于预防和/或治愈这种使人衰弱的矿化组织疾病的有效靶向疗法。在 此外，阐明指导 H2O 的分子信号也可用于设计更有效的策略 以受控和定向的方式再生骨骼。 拟议研究的重要性以及与公共卫生的相关性包括骨骼和 仅在美国，就有多达七百个活产婴儿中就有一个出现颅面缺陷，这使其成为一个严重的问题 健康问题。此外，在其他人类疾病中也观察到过氧化氢，例如钙化性心脏瓣膜病和 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。