A BABOON MODEL FOR THE GENETICS OF CORTICAL BONE MATERIAL PROPERTIES

皮质骨材料特性遗传学的狒狒模型

• 批准号: 7393205
• 负责人: LORENA M HAVILL
• 金额: $ 16.26万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393205
• 关键词: Adult; Affect; Age; Architecture; Arthritis; Attention; Behavior; Biology; Bone Density; Bone Mineral Contents; Bone Tissue; Complex; Condition; Data; Disease; Early identification; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Failure; Female; Femur; Foundations; Fracture; Future; Genes; Genetic; Genetic Models; Goals; H2 gene; Health; Health Care Costs; Heritability; Human; Incidence; Individual; Institutes; Investigation; Lead; Localized; Measurable; Measures; Mission; Modeling; Musculoskeletal; Neck; Numbers; Osteoporosis; Pain; Papio; Pathogenesis; Persons; Phenotype; Phylogenetic Analysis; Physiology; Population; Postmenopausal Osteoporosis; Predisposition; Prevention; Primates; Property; Proxy; Public Health; Quantitative Trait Loci; Regulation; Relative (related person); Reporting; Research; Research Project Grants; Residual state; Resistance; Risk; Rodent; Role; Serum; Skeletal system; Stress; Study models; Support of Research; Testing; Time; Tissues; Variant; Work; age effect; age related; base; bone; bone quality; bone strength; bone turnover; density; genome-wide linkage; improved; male; mineralization; nonhuman primate; osteoporosis with pathological fracture; sex; skin disorder; substantia spongiosa; thoracic vertebra bone structure; trend

DESCRIPTION (provided by applicant): Until recently, a majority of studies of bone fracture resistance focused on bone mass. However, epidemiological studies now suggest that a significant proportion of fracture risk is independent of bone mass. In addition to the effects of age and sex, proxy measures of bone strength (e.g. bone mineral content and density) consistently show significant genetic effects. While genetic studies of bone material properties have been conducted in rodents, similar studies have not been done in humans or other primates. Substantial differences in fracture properties between other species and primates underscore the need for a genetically well-characterized non-human primate model for studies of the genetics of bone material properties. We propose to investigate the contribution of genes to cortical bone material properties, direct measures of bone quality that are essential aspects of a bone's structural integrity. The ultimate objective of the proposed study is to establish the baboon as a model for the genetic study of human bone material properties. Using data collected from the right femur of 100 pedigreed adult baboons, the specific aims of this project are to: 1) determine cortical bone tissue properties including elastic modulus, yield and ultimate strength, post-yield behavior, fracture toughness, and mineralization (ash fraction and microCT-determined bone mineral density) and determine the degree to which cortical bone density and mineralization (ash fraction) are correlated to cortical bone material properties; 2) characterize normal variation, including age and sex effects, on cortical bone material properties in the baboon; and 3) detect and quantify the proportion of variation in these properties that is due to the additive effects of genes. We will assess the relative magnitude of the effect of genes on cortical bone properties as determined in this project vs. trabecular bone material properties determined from other research. Demonstrating that cortical bone material properties are heritable is an essential step leading to future studies to detect, localize, and identify the specific genes that effect these properties in the baboon. Phylogenetic proximity and consequent similarities in skeletal physiology and genetics between baboons and humans inspire confidence that these results will be directly relevant to humans. This project is consistent with the National Institute of Arthritis and Musculoskeletal and Skin Diseases' mission of supporting research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases as the goal is to establish a non-human primate model that will lead, ultimately, to improved understanding of the genetic regulation of bone material properties that will facilitate earlier identification of persons at greater risk for fracture (due to osteoporosis-associated skeletal fragility), and allow earlier implementation of prevention and treatment strategies. Osteoporosis is an age-related health problem of immediate public health concern that results in 1.5 million fractures in the U.S. each year. A great deal of the risk of osteoporotic fracture is due to genes. We propose to develop the baboon as a nonhuman primate model for the genetics of cortical bone fragility in humans. Establishment of this model will lead, ultimately, to improved understanding of the genetic regulation of these material properties, thereby facilitating earlier identification of persons at greater risk for fracture, and allowing for earlier implementation of prevention and treatment strategies.

描述（由申请人提供）：直到最近，大多数抗骨折性研究都集中在骨量上。然而，流行病学研究现在表明，骨折风险的一个显着比例是独立的骨量。除了年龄和性别的影响外，骨强度的替代指标（例如骨矿物质含量和密度）始终显示出显着的遗传效应。虽然已经在啮齿动物中进行了骨骼材料特性的遗传研究，但还没有在人类或其他灵长类动物中进行类似的研究。其他物种和灵长类动物之间的骨折特性的实质性差异强调了需要一个遗传特征良好的非人灵长类动物模型，用于骨材料特性的遗传学研究。我们建议研究基因对皮质骨材料特性的贡献，直接测量骨质量，这是骨结构完整性的重要方面。本研究的最终目的是建立狒狒作为人类骨材料特性遗传研究的模型。利用从100只纯种成年狒狒右股骨收集的数据，该项目的具体目标是：1）确定皮质骨组织性质，包括弹性模量、屈服和极限强度、屈服后行为、断裂韧性，和矿化（灰分分数和microCT测定的骨矿物质密度），并确定皮质骨密度和矿化程度（灰分分数）与皮质骨材料性质相关; 2）表征狒狒中皮质骨材料性质的正常变化，包括年龄和性别效应;和3）检测和量化由于基因的加性效应引起的这些性质的变化的比例。我们将评估基因对本项目中确定的皮质骨性质与其他研究确定的松质骨材料性质的影响的相对大小。证明皮质骨材料的特性是可遗传的，这是导致未来研究检测、定位和鉴定影响狒狒这些特性的特定基因的重要一步。狒狒和人类在骨骼生理学和遗传学方面的系统发育接近性和随之而来的相似性激发了人们的信心，即这些结果将与人类直接相关。该项目与国家关节炎、肌肉骨骼和皮肤疾病研究所的使命一致，即支持对关节炎、肌肉骨骼和皮肤疾病的病因、治疗和预防的研究，其目标是建立一个非人类灵长类动物模型，最终，提高对骨材料特性的遗传调节的理解，这将有助于更早地识别年龄较大的人。骨折的风险（由于骨质疏松相关的骨骼脆弱性），并允许早期实施预防和治疗策略。骨质疏松症是一种与年龄相关的健康问题，直接引起公众健康关注，每年在美国导致150万例骨折。很大程度上，骨质疏松性骨折的风险是由于基因。我们建议开发狒狒作为一个非人灵长类动物模型的遗传学在人类皮质骨脆性。这一模型的建立将最终导致更好地了解这些物质特性的遗传调节，从而促进早期识别骨折风险较大的人，并允许早期实施预防和治疗战略。