Developmental Mechanisms for the Evolution of Bone Loss

骨质流失演变的发育机制

• 批准号: 7617619
• 负责人: JOHN H. POSTLETHWAIT
• 金额: $ 48.92万
• 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/7617619
• 关键词: Accounting; Affect; Age; Americas; Animals; Antarctic; Bladder; Bone Density; Candidate Disease Gene; Cartilage; 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; 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）：包括骨质疏松症在内的骨质流失疾病是对美国老龄化人口的巨大威胁。退化性骨质减少症是一种具有环境和遗传成分的复杂性状，并且可能是由于自然选择强度的降低而产生的，从而在后生殖个体中保持稳健的骨产生。这种复杂性状的自然变异存在于某些脊椎动物谱系中，从而导致继发性骨质减少的适应性演变。我们将针对人类疾病的进化突变模型的创新策略应用于骨质减少南极鱼的骨骼，其祖先具有强大的骨骼。随着对南极鱼的某些谱系中的浓骨的自然选择减少，骨骼变成了骨质减少剂，使动物可以居住在水柱上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。拟议工作的目的是表征具有骨质减少骨骼和正常骨骼的物种之间的遗传和表型差异，从而确定了人类骨变性疾病的新候选基因和机制。我们的假设是，下调基因活性的突变阳性地调节成骨的基因或上调基因的活性，这些基因的活性对成骨的影响造成了与骨质减少骨骼相关的相关物种的发展差异，而骨质减少剂与可靠的骨骼相关物种的差异。 AIM 1将确定骨骼发育在骨质减少物种Chaenocephalus aceratus（Blackfin Ice Fish）与使用软骨，骨骼和细胞外基质分子的骨骼和骨骼骨骼标记的相关物种Notothenia coriiceicps（Yellowbelly Rock Cod）之间相关的相关物种Notothenia coriiceIceps（Yellowbelly Rock Cod）在骨骼发育之间发育的阶段。 AIM 2将使用高吞吐量cDNA测序来比较来自密集和骨质较差的物种的骨骼发育组织的基因表达谱图，以识别这两种物种之间的调节差异。 AIM 3将使用功能的损失和功能获得实验来定义骨骼调节基因在骨骼骨骼发展中的功能作用。 Stickleback是一种与我们南极鱼有关的模型物种，具有完全测序的基因组，并且适合实验室中的基因敲低和转基因。 意义：这些实验将揭示其在自然选择的作用下改变的基因的身份和功能，以减少南极鱼类的骨骼骨化。由于在发育时间内骨骼矿化的减少在进化时代模仿了人类骨质流失疾病，因此这些研究具有鉴定新基因的潜力，并为骨质骨质疏松症，骨质疏松症和其他骨浪费障碍的机制提供新的见解，这些疾病可以利用人类疾病的新疗法。 项目叙述：拟议的实验将揭示基因的身份和功能，其在自然选择的作用下，其活性发生了变化，从而导致南极鱼某些谱系中骨矿物质密度的丧失。由于南极鱼类骨矿化的减少，而南极鱼类的进化时间却模仿了人类随着发育时间的年龄的增长而降低骨密度，因此拟议的研究有可能识别新基因，并为低骨矿物质密度，骨质疏松症以及其他造成人类疾病的骨骼密度，骨质浪费障碍的机制提供新的见解，以开发人类的新型疾病。