The zebrafish mutant droog as a model for human osteoporosis

斑马鱼突变体 droog 作为人类骨质疏松症模型

• 批准号: 8774474
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774474
• 关键词: Adult; Adverse effects; Affect; Age; Alleles; Animal Model; Bone Density; Bone Development; Bone Diseases; Candidate Disease Gene; Cell Culture Techniques; Cells; Chemicals; Defect; Development; Diabetes Mellitus; Diet; Differentiation Antigens; Disease; Exhibits; Fracture; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Goals; Harvest; Health; Health Priorities; Homeostasis; Human; In Vitro; Knowledge; Lead; Medical; Menopausal Status; Messenger RNA; Metabolic Bone Diseases; Mission; Modeling; Molecular; Mutagenesis; Mutation; Nature; Osteoclasts; Osteopenia; Osteoporosis; Osteoporosis prevention; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physical activity; Population; Predisposition; Prevention; Proteins; Public Health; Quality of life; Research; Risk; Series; Siblings; Skeletal Development; Staging; Time; Tissue Differentiation; Tissue Engineering; Tissues; Variant; Woman; Zebrafish; aged; base; bone loss; cost; drug discovery; effective therapy; gene function; genome wide association study; human disease; improved; in vivo; innovation; men; mutant; new therapeutic target; next generation sequencing; novel; osteoporosis with pathological fracture; prevent; public health relevance; repaired; screening; sex; skeletal; skeletal disorder; small molecule; spine bone structure; success; tool

DESCRIPTION (provided by applicant): Bone fractures due to osteoporosis present a significant public health burden, high medical costs, and reduced quality of life in an increasingl aged population. It is estimated that 40-90% of variation in BMD may be due to genetic variability. Although more than 40 candidate genes for predisposition to osteoporosis have been identified, they represent less than 1% of the genetic variance of BMD at the population level, due to the large number of genes functioning in bone development and homeostasis. These studies identify osteoporosis as a major health problem, and emphasize the need for further research and better animal models to elucidate genetic factors underlying this disease. In the proposed studies, we will define the molecular and developmental nature of the newly identified zebrafish osteopenia mutant, droog(dro)tft92N, as a novel animal model for human osteoporosis. This research is significant and innovative in that it may implicate a new gene in the prevention of osteoporosis. In addition, these studies will validate the zebrafish mutant dro as a new model to improve our understanding of the genetic contributions leading to human osteoporosis, and as an in vivo screening tool to identify new therapeutic targets to treat human osteoporosis. Our proposed studies to establish a three dimensional (3D) in vitro cell culture model to study normal and dro mutant harvested cells will provide an innovative platform for small molecular screens to identify novel therapies for improved and effective treatment of human osteoporosis.

描述（由申请人提供）：骨质疏松症引起的骨折给日益增长的老龄化人口带来了巨大的公共健康负担、高昂的医疗费用和生活质量下降。据估计，40-90% 的 BMD 变异可能是由于遗传变异造成的。尽管已鉴定出 40 多个易患骨质疏松症的候选基因，但由于大量基因在骨骼发育和体内平衡中发挥作用，因此它们在人群水平上仅占 BMD 遗传变异的不到 1%。这些研究将骨质疏松症确定为一个主要的健康问题，并强调需要进一步的研究和更好的动物模型来阐明这种疾病背后的遗传因素。在拟议的研究中，我们将定义新发现的斑马鱼骨质减少突变体 droog(dro)tft92N 的分子和发育性质，作为人类骨质疏松症的新型动物模型。这项研究具有重要意义和创新性，因为它可能涉及预防骨质疏松症的新基因。此外，这些研究将验证斑马鱼突变体dro作为一种新模型，以提高我们对导致人类骨质疏松症的遗传贡献的理解，并作为体内筛选工具来确定治疗人类骨质疏松症的新治疗靶点。我们提出的建立三维（3D）体外细胞培养模型来研究正常和dro突变体收获细胞的研究将为小分子筛选提供一个创新平台，以确定改进和有效治疗人类骨质疏松症的新疗法。