GENETIC DETERMINATION OF SKELETAL FRAGILITY

描述(改编自申请人的摘要)：本报告的目的 研究是确定骨骼脆性和骨质疏松症 导致骨折的结构和成分特性。 A/J近交系小鼠表现出显著减少的屈服后变形(a 在全骨弯曲试验中与股骨的比较 取自C57BL/6J小鼠。调查人员假设， A/J和C57BL/6J之间的骨断裂性能是由遗传因素引起的 确定了基质结构和组成的变化。为了测试这一点 假设，他将首先确定组织学和成分 导致A/J之间机械差异的属性 和C57BL/6J股骨，通过实验测量骨折和损伤 在整个骨骼和组织水平上的机制，并比较 结果与组织结构和成分参数有关。第二，他 将进行遗传分析，使用重组的自交系和共生体 菌株，以确定导致基因差异的基因数量 断裂行为，或许还能确定候选基因。第三，他会 确定导致A/J表型的基质改变是否为 通过量化股骨的结构和组成来继承 表现A/J表型的重组菌株和共生体菌株。最终， 申请者的目标是为 从几个方面理解骨骼脆性：(1)识别 破坏正常骨折行为的组织结构改变 将为诊断正常个体提供另一种依据 有骨折风险的人群；(2)确定遗传联系 组织结构和改变的断裂性能之间的关系提供了 为未来的研究奠定基础，这些研究将确定基因的细微变化 表达是中介的(例如，体力活动、营养、激素 状态、突变等)；以及(3)确定骨骼的遗传基础 脆弱性可能会导致对如何定制治疗的更好理解 适应那些抵制传统的个人的方式 治疗策略。

DESCRIPTION (Adapted from the Applicant's Abstract): The purpose of this study is to determine the genetic link between skeletal fragility and the structural and compositional properties which contribute to bone fracture. A/J inbred mice exhibit significantly reduced post-yield deformation (a measure of bone brittleness) in whole bone bending tests compared to femurs from C57BL/6J mice. The investigator hypothesizes that the difference in bone fracture properties between A/J and C57BL/6J are due to genetically determined variations in matrix structure and composition. To test this hypothesis, he will first identify the histological and compositional properties that are responsible for the mechanical differences between A/J and C57BL/6J femurs, by experimentally measuring fracture and damage mechanisms, at both the whole bone and the tissue level, and comparing the results with tissue organization and composition parameters. Second, he will conduct a genetic analysis, using recombinant inbred and consomic strains, to determine the number of genes responsible for the differences in fracture behavior and, perhaps, identify candidate genes. Third, he will determine if the matrix alterations responsible for the A/J phenotype are inherited by quantifying the structure and composition of femurs for the recombinant and consomic strains exhibiting the A/J phenotype. Ultimately, the applicant's goal is to make significant contributions to the understanding of skeletal fragility in several ways: (1) identifying alterations in tissue organization which disrupt normal fracture behavior will provide an alternative basis for diagnosis of individuals in the normal population who are at risk of fracture; (2) identifying a genetic link between tissue organization and altered fracture properties provides the basis for future studies which identify how subtle variations in genetic expression are mediated (e.g., physical activity, nutrition, hormonal status, mutations, etc.); and (3) identifying a genetic basis for skeletal fragility may lead to a better understanding of how to customize treatment modalities to accommodate those individuals who are resistant to traditional treatment strategies.