Developmental Mechanisms for the Evolution of Bone Loss

骨质流失演变的发育机制

• 批准号: 8067802
• 负责人: JOHN H. POSTLETHWAIT
• 金额: $ 47.1万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067802
• 关键词: Accounting; Affect; Age; Americas; Animals; Antarctic; Bladder; Bone Density; Bone Matrix; Candidate Disease Gene; Cartilage; Cartilage Matrix; Cephalic; Cods; Complementary DNA; Complex; Degenerative Disorder; Dermal; Development; Disease; Evolution; Expressed Sequence Tags; Extinction (Psychology); Extracellular Matrix; Fishes; Floor; Gasterosteidae; Gene Expression; Gene Transfer Techniques; Genes; Genetic; Goals; Growth; Human; Human Development; Ice; In Situ Hybridization; Individual; Laboratories; Modeling; Molecular Genetics; Molecular Profiling; Mutation; Natural Selections; Oceans; Orthologous Gene; Osteogenesis; Osteopenia; Osteoporosis; Pathway interactions; Patients; Pattern; Pelvis; Physiologic calcification; Play; Production; Proteins; Regulator Genes; Resources; Role; Schedule; Sister; Skeletal Development; Skeleton; Staging; Staining method; Stains; Swimming; System; Testing; Time; Time Study; Tissues; Variant; Vertebral column; Wasting Syndrome; Water; Work; aging population; base; bone; bone loss; cranium; demineralization; gain of function; gene function; genome sequencing; human disease; innovation; insight; loss of function; member; mutant; novel; osteogenic; reproductive; research study; skeletal; skeletal tissue; skeletogenesis; software development; teleost; trait; wasting

DESCRIPTION (provided by applicant): Bone loss diseases, including osteoporosis, are a significant and increasing threat for America's aging population. Degenerative osteopenia is a complex trait with environmental and genetic components, and may have arisen from a reduction in the strength of natural selection to maintain robust bone production in post- reproductive individuals. Natural variation for this complex trait exists in certain vertebrate lineages leading to the adaptive evolution of secondary osteopenia. We apply the innovative strategy of evolutionary mutant models for human disease to the skeletons of osteopenic Antarctic fish, whose ancestors possessed robust skeletons. As natural selection for dense bones diminished in certain lineages of Antarctic fish, the skeleton became osteopenic, allowing animals to inhabit the water column and exploit its abundant resources. Related lineages that retain dense skeletons continue to forage on the ocean floor. The goal of the proposed work is to characterize the genetic and phenotypic differences between species with osteopenic and normal skeletons, and thereby identify new candidate genes and mechanisms for human bone degeneration diseases. Our hypothesis is that mutations that either down-regulate the activity of genes that positively regulate osteogenesis or up-regulate the activity of genes that negatively affect osteogenesis account for evolved differences in related species with osteopenic versus robust skeletons. Aim 1 will identify the stages at which skeletal development diverges between the osteopenic species Chaenocephalus aceratus (blackfin ice fish) and the related robustly ossified species Notothenia coriiceps (yellowbelly rock cod) using stains for cartilage, bone, and extracellular matrix molecules, and the expression of skeletal marker genes. Aim 2 will use high- throughput cDNA sequencing to compare gene expression profiles of skeletogenic tissues from densely and poorly ossified species as a means to identify regulatory differences between the two species. Aim 3 will define the functional roles of skeletal regulatory genes in the development of the ossified skeleton using loss- of-function and gain-of-function experiments in three-spine stickleback. Stickleback, a model species related to our Antarctic fish, has a completely sequenced genome, and is amenable to gene knockdown and transgenesis in the laboratory. Significance: These experiments will reveal the identities and functions of genes whose activities have changed, under the force of natural selection, to reduce skeletal ossification in Antarctic fish. Because the reduction of bone mineralization over evolutionary time mimics human bone loss diseases over developmental time, these studies have the potential to identify new genes, and provide new insights into mechanisms for osteopenia, osteoporosis, and other bone wasting disorders that can be exploited to develop novel therapies for human disease. Project Narrative: The proposed experiments will reveal the identities and functions of genes whose activities have changed, under the force of natural selection, leading to loss of bone mineral density in certain lineages of Antarctic fish. Because the reduction of bone mineralization over evolutionary time in Antarctic fish mimics the reduction of bone density in humans as they age over developmental time, the proposed studies have the potential to identify new genes, and provide new insights into mechanisms for low bone mineral density, osteoporosis, and other bone wasting disorders that can be exploited to develop novel therapies for human disease.

描述（由申请人提供）：骨质流失疾病，包括骨质疏松症，是美国老龄化人口日益严重的威胁。退行性骨质减少是一种具有环境和遗传成分的复杂特征，可能是由于生殖后个体维持强健骨生成的自然选择强度降低所致。这种复杂性状的自然变异存在于某些脊椎动物谱系中，导致继发性骨质减少的适应性进化。我们将人类疾病的进化突变模型的创新策略应用于骨质减少的南极鱼类的骨骼，其祖先拥有强健的骨骼。由于某些南极鱼类的自然选择减少了，骨骼变得少骨，使动物能够栖息在水柱中并利用其丰富的资源。保留密集骨骼的相关谱系继续在海底觅食。这项工作的目的是表征骨减少和正常骨骼物种之间的遗传和表型差异，从而确定人类骨退行性疾病的新候选基因和机制。我们的假设是，突变要么下调积极调节成骨的基因活性，要么上调对成骨产生负面影响的基因活性，这解释了相关物种骨骼减少与强壮的进化差异。目的1将利用软骨、骨骼和细胞外基质分子染色以及骨骼标记基因的表达，确定骨质减少物种Chaenocephalus aceratus（黑鳍冰鱼）和相关的强壮骨化物种Notothenia coriiceps（黄腹岩鳕鱼）之间骨骼发育分化的阶段。目的2将使用高通量cDNA测序来比较密集和低骨化物种的成骨组织的基因表达谱，作为鉴定两种物种之间调节差异的手段。目的3将使用三棘棘鱼的功能丧失和功能获得实验来定义骨骼调节基因在骨化骨骼发育中的功能作用。棘鱼是一种与南极鱼类有亲缘关系的模式物种，具有完全测序的基因组，并且可以在实验室中进行基因敲除和转基因。