Genetic Determination of Skeletal Fragility

骨骼脆弱性的遗传决定

• 批准号: 8737389
• 负责人: KARL J JEPSEN
• 金额: $ 7.41万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737389
• 关键词: Adult; Affect; Age; Architecture; Biological; Biological Factors; Biological Process; Biological feedback; Biology; Bone Development; Bone Substitutes; Bone Surface; Buffers; Carrying Capacities; Child; Chromosomes; Clinical; Complex; Congenic Strain; Consomic Strain; Control Groups; Data; Detection; Development; Elderly; Endocrine; Engineering; Environment; Exercise; Female; Femur; Fracture; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Growth; Growth Factor; Health; Inbred Strain; Inbreeding; Individual; Lead; Length; Life; Maps; Measurable; Mechanics; Modeling; Operating System; Organ; Pattern; Phenotype; Physiological; Predisposition; Property; Protocols documentation; Quantitative Trait Loci; Relative (related person); Resistance; Risk; Risk Reduction; Serum; Signal Transduction; Skeleton; Structure; System; Testing; Thick; Tissues; Variant; Width; Work; base; bone; bone mass; congenic; design; genetic variant; genome-wide; improved; insight; long bone; male; mineralization; novel; public health relevance; research study; response; skeletal; theories; trait; young adult

DESCRIPTION (provided by applicant): Our goal for the competing renewal is to better understand how phenotypic covariation contributes to the genetic basis of skeletal fragility. Preliminary studies indicate that sets of adult traits are established during post-natal growth through functional interactions between matrix mineralization and bone surface expansions. Further, these functional relationships, which were consistent with current theories of how a strain-based biological feedback system operates, were deterministic of adult bone functionality and fragility. We hypothesize that phenotypic covariation is a genetically determined trait that simultaneously coordinates essential aspects of bone biology to match loading demands during development. We propose to test this hypothesis by mapping quantitative trait loci (QTLs) that alter phenotypic covariation (Aim 1) using C57BL/6J-ChrA/J Chromosome Substitution Strains (CSSs). Further, we hypothesize that allelic variants that alter phenotypic covariation result from an altered responsiveness to mechanical loading. We test this hypothesis by determining whether QTLs regulating phenotypic covariation and the adaptive response to exercise map to the same genomic regions (Aims 2, 3). Finding this association would mean that skeletal growth patterns could be used as a predictor of the responsiveness of bone to mechanical loading. Finally, we propose to systematically assess each level of structural hierarchy in order to assign biological functionality to the QTLs. To accomplish this, we combine QTL analyses with quantitative analyses of cellular activity and serum growth factors. Many CSSs will show alterations in a specific trait or a specific trait interaction, and this is expected to be associated with measurable changes in endocrine signals during growth. This genetic perturbation experiment thus allows us to seek a biological factor that acts as a common control coordinating cellular activities during growth (i.e., functional adaptation). We will focus on the GH/IGF axis since this is the primary determinant of post-natal growth. These studies will not only identify novel QTLs regulating trait interactions during growth, but the results should also provide important insight into how functional adaptation buffers the deleterious mechanical consequences of genetic variants leading to slender bone phenotypes.

描述（由申请人提供）：我们竞争性更新的目标是更好地了解表型协变如何影响骨骼脆弱性的遗传基础。初步研究表明，成年性状集建立在出生后的增长，通过功能之间的相互作用基质矿化和骨表面扩张。此外，这些功能关系与基于应变的生物反馈系统如何运作的当前理论一致，是成人骨功能和脆性的决定性因素。我们假设，表型协变是一种遗传决定的性状，同时协调骨生物学的重要方面，以匹配在发展过程中的负荷需求。本研究利用C57 BL/6 J-ChrA/J染色体置换株系（CSSs）定位改变表型协变（Aim 1）的数量性状基因座（QTL）来验证这一假设。此外，我们假设等位基因变异改变表型协变的结果从改变响应机械负荷。我们通过确定调节表型协变和运动适应性反应的QTL是否映射到相同的基因组区域来检验这一假设（目的2，3）。发现这种关联意味着骨骼生长模式可以作为骨骼对机械负荷反应的预测因子。最后，我们建议系统地评估每个层次的结构层次，以分配生物功能的QTL。为此，我们将联合收割机QTL分析与细胞活性和血清生长因子的定量分析相结合。许多CSS将显示特定性状或特定性状相互作用的改变，预计这与生长期间内分泌信号的可测量变化有关。因此，该遗传扰动实验允许我们寻找在生长期间充当协调细胞活动的共同控制的生物因子（即，功能适应）。我们将专注于GH/IGF轴，因为这是产后生长的主要决定因素。这些研究不仅将确定新的QTL调节性状在生长过程中的相互作用，但结果也应该提供重要的洞察功能适应如何缓冲有害的机械后果的遗传变异，导致骨骼纤细的表型。