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: 7256732
• 负责人: LORENA M HAVILL
• 金额: $ 21.44万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256732
• 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，大多数抗骨折研究都集中在骨量上。然而，现在的流行病学研究表明，很大一部分骨折风险与骨量无关。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影响。虽然已经在啮齿类动物中进行了骨材料特性的遗传研究，但尚未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骨折特性的巨大差异强调需要一个具有良好遗传特征的非人类灵长类动物模型来研究骨材料特性的遗传学。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。该研究的最终目标是建立狒狒作为人类骨骼材料特性遗传研究的模型。使用从 100 只纯种成年狒狒的右股骨收集的数据，该项目的具体目标是：1) 确定皮质骨组织特性，包括弹性模量、屈服强度和极限强度、屈服后行为、断裂韧性和矿化（灰分和 microCT 确定的骨矿物质密度），并确定皮质骨密度和矿化（灰分）与皮质骨材料的相关程度 特性; 2) 描述狒狒皮质骨材料特性的正常变化，包括年龄和性别影响； 3) 检测并量化这些特性中由于基因的加性效应而产生的变异比例。我们将评估本项目中确定的基因对皮质骨特性的影响与其他研究确定的小梁骨材料特性的相对大小。证明皮质骨材料特性是可遗传的，是未来研究检测、定位和识别影响狒狒这些特性的特定基因的重要一步。狒狒和人类之间的系统发育接近性以及随之而来的骨骼生理学和遗传学相似性激发了人们的信心，即这些结果将与人类直接相关。该项目符合国家关节炎、肌肉骨骼和皮肤疾病研究所的使命，即支持关节炎、肌肉骨骼和皮肤疾病的病因、治疗和预防研究，目标是建立一个非人类灵长类动物模型，最终将提高对骨材料特性的遗传调控的理解，从而有助于更早识别骨折风险较高的人（由于 骨质疏松症相关的骨骼脆弱性），并允许更早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，引起了公众的直接关注，每年在美国导致 150 万例骨折。骨质疏松性骨折的很大一部分风险是由基因造成的。我们建议将狒狒开发为人类皮质骨脆性遗传学的非人类灵长类动物模型。该模型的建立最终将提高对这些材料特性的基因调控的理解，从而有助于更早识别骨折风险较高的人，并尽早实施预防和治疗策略。