Bone Structural Integrity Profiling to Advance Skeletal Genetics and Biomechanics
骨结构完整性分析以推进骨骼遗传学和生物力学
基本信息
- 批准号:8301575
- 负责人:
- 金额:$ 71.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-15 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdherenceAffectAgeAreaBehaviorBiologicalBiomechanicsBody SizeBone DensityBone TissueCharacteristicsComplexComputer SimulationDescriptorDevelopmentDiseaseEnvironmentExhibitsFemaleFemurFractureFutureGene Expression ProfileGenesGeneticGenetic VariationGoalsH2 geneHealthHeritabilityIndividualKnowledgeLengthLinkMaintenanceMeasuresMechanicsMediatingMethodsMolecularMorphologyMusculoskeletalOsteoporosisPapioPathway AnalysisPatternPerformancePopulationPrincipal Component AnalysisProcessPropertyPublic HealthResearch DesignResistanceRiskRoleShapesSimulateSpeedStructureTestingTherapeuticTissuesVariantWorkage effectage relatedbonebone qualitybone strengthdesignfallsgene discoveryimprovedmalesexskeletalsubstantia spongiosatrait
项目摘要
DESCRIPTION (provided by applicant): The structural integrity of bone in any mechanical loading environment is an integrative function of a multitude of complex and interrelated characteristics of bone at the macro-, micro- and ultrastructural levels of bone's structural organization. Bone fragility and increased fracture risk result from multiple, distinct combinations of scores of bone traits. A dynamic process of co-adaptation of traits provides for redundant combinations of traits through which structures are produced that provide adequate functionality under "normal" loading conditions. However, some of these combinations of traits can result in structures that are suboptimal when subjected to atypical or traumatic loads, such as those encountered in a fall. The dominant study design in skeletal genetics and biomechanics focuses on the role of one or a limited set of morphological and/or compositional factors in bone fragility. This approach is effective for identifying discrete traits that contribute to bone fracture resistance, but we cannot get a complete picture of the mechanobiological processes underlying fracture risk without a more comprehensive study design that captures variation at each of bone's hierarchical levels, since all of these traits work synergistically to control fracture risk. We propose a multi-disciplinary, integrative approach that is a major departure from traditional approaches to skeletal biomechanics and genetics. Our study is designed to identify composite traits comprising uncorrelated expression patterns of specific measures of bone quality and density that are linked to bone structural performance, to estimate the heritability (h2) of these composite traits, and to prioritize genes and gene networks most likely to affect fracture risk. Specifically, we aim to 1) measure a thorough suite of bone traits in the femurs of 100 pedigreed baboons, then use variable reduction methods to distill the multitude of interrelated, highly correlated traits down to a small set of uncorrelated descriptors of variation in bone morphology and composition. Hypothesis: There is a set of uncorrelated, composite traits that efficiently disentangles the elaborate network of compositional and morphological traits responsible for population-level normal variation in bone biomechanical behavior. 2) Characterize age and sex effects on these composite traits, 3) Assess femoral apparent biomechanical properties under normal and non-habitual loading conditions. Hypothesis: Differential expression of these traits in individuals results in structures that support normal functional musculoskeletal activities, a subset of which perform poorly when loaded in a non-habitual manner. 4) Detect and quantify the proportion of variation in each composite descriptor that is due to the additive effects of genes (h2), and 5) Identify genes and networks that are differentially active in bone tissue from strong for size vs. weak for size femurs. Such fundamental knowledge would allow for development of vastly improved preventative and therapeutic strategies for osteoporosis-related fractures.
描述(由申请人提供):在任何机械载荷环境下,骨的结构完整性是骨结构组织的宏观、微观和超微结构水平上众多复杂和相互关联的特征的综合功能。骨脆弱性和骨折风险的增加是由多种不同的骨骼特征组合而成的。性状共同适应的动态过程提供了性状的冗余组合,通过这些组合产生的结构在“正常”负载条件下提供足够的功能。然而,当遭受非典型或创伤性载荷时,例如在跌倒时,这些特征的一些组合可能导致结构不理想。骨骼遗传学和生物力学的主要研究设计集中在一个或一组有限的形态学和/或组成因素在骨骼脆性中的作用。这种方法对于识别有助于骨骼抗骨折的离散特征是有效的,但如果没有更全面的研究设计来捕捉每个骨骼层次水平的变化,我们就无法全面了解骨折风险的机械生物学过程,因为所有这些特征都协同工作以控制骨折风险。我们提出了一种多学科、综合的方法,这是对骨骼生物力学和遗传学传统方法的重大背离。我们的研究旨在确定复合性状,包括与骨结构性能相关的骨质量和密度的特定测量的不相关表达模式,估计这些复合性状的遗传力(h2),并优先考虑最可能影响骨折风险的基因和基因网络。具体来说,我们的目标是1)测量100只纯种狒狒股骨的一套完整的骨骼特征,然后使用变量约简方法将大量相互关联的、高度相关的特征提炼成一小组不相关的骨骼形态和组成变异描述符。假设:存在一组不相关的复合特征,有效地解开了构成和形态特征的复杂网络,这些特征负责骨骼生物力学行为的人群水平正常变化。2)表征年龄和性别对这些综合性状的影响;3)评估正常和非习惯性负荷条件下股骨的表观生物力学特性。假设:这些特征在个体中的差异表达导致支持正常功能肌肉骨骼活动的结构,其中一部分在非习惯方式下表现不佳。4)检测并量化每个复合描述符中由基因加性效应引起的变异比例(h2); 5)识别骨组织中因股骨大小而强与因股骨大小而弱的基因和网络。这些基础知识将极大地改善骨质疏松相关骨折的预防和治疗策略。
项目成果
期刊论文数量(0)
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LORENA M HAVILL其他文献
LORENA M HAVILL的其他文献
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{{ truncateString('LORENA M HAVILL', 18)}}的其他基金
Bone Structural Integrity Profiling to Advance Skeletal Genetics and Biomechanics
骨结构完整性分析以推进骨骼遗传学和生物力学
- 批准号:
8187565 - 财政年份:2011
- 资助金额:
$ 71.38万 - 项目类别:
Bone Structural Integrity Profiling to Advance Skeletal Genetics and Biomechanics
骨结构完整性分析以推进骨骼遗传学和生物力学
- 批准号:
8471655 - 财政年份:2011
- 资助金额:
$ 71.38万 - 项目类别:
A PEDIGREED BABOON MODEL FOR THE GENETICS OF CORTICAL BONE MATERIAL PROPERTIES
皮质骨材料特性遗传学的纯种狒狒模型
- 批准号:
7716121 - 财政年份:2008
- 资助金额:
$ 71.38万 - 项目类别:
IDENTIFYING POLYMORPHISMS IN THE LRP5 GENE IN BABOONS
鉴定狒狒 LRP5 基因的多态性
- 批准号:
7716122 - 财政年份:2008
- 资助金额:
$ 71.38万 - 项目类别:
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 - 财政年份:2007
- 资助金额:
$ 71.38万 - 项目类别:
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 - 财政年份:2007
- 资助金额:
$ 71.38万 - 项目类别:
GENETICS OF TRABECULAR BONE RESISTANCE TO FRACTURE IN VERTEBRAE
椎骨骨小梁抗骨折的遗传学
- 批准号:
7349856 - 财政年份:2006
- 资助金额:
$ 71.38万 - 项目类别:
GENETICS OF SEX EFFECTS ON BONE DENSITY AND TURNOVER
性别遗传学对骨密度和更新的影响
- 批准号:
7349837 - 财政年份:2006
- 资助金额:
$ 71.38万 - 项目类别:
PROBABILISTIC SHAPE-BASED FINITE ELEMENT MODELING OF BABOON FEMURS
基于概率形状的狒狒股骨有限元建模
- 批准号:
7349857 - 财政年份:2006
- 资助金额:
$ 71.38万 - 项目类别:
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