GENETIC DETERMINATION OF SKELETAL FRAGILITY

描述（改编自申请人的摘要）：本申请的目的是 这项研究的目的是确定骨骼脆弱性与 导致骨折的结构和成分特性。 A/J近交系小鼠表现出显著降低的屈服后变形（a 骨脆性的测量）在全骨弯曲试验中与股骨相比 来自C57 BL/6 J小鼠。 研究人员假设， A/J和C57 BL/6 J之间的骨折性质是由于遗传原因造成的。 确定基质结构和组成的变化。 为了验证这一 假设，他将首先确定组织学和成分 导致A/J之间机械差异的性能 和C57 BL/6 J股骨的骨折和损伤 机制，在整个骨和组织水平，并比较 结果与组织组织和成分参数。 二是他 将进行遗传分析，使用重组近交系和染色体 菌株，以确定负责差异的基因数量， 骨折行为，也许，确定候选基因。 第三，他将 确定负责A/J表型的基质改变是否 通过量化股骨的结构和组成来继承， 显示A/J表型的重组和同源体菌株。 最后， 申请人的目标是为社会做出重大贡献。 从几个方面了解骨骼脆弱性：（1）识别 破坏正常骨折行为的组织结构改变 将提供一个替代的基础上诊断个人在正常的 有骨折风险的人群;（2）确定遗传联系 组织结构和改变的骨折特性之间的联系， 为未来的研究奠定了基础， 表达是介导的（例如，体力活动，营养，荷尔蒙 状态、突变等）;和（3）确定骨骼肌的遗传基础 脆弱性可能会导致更好地理解如何定制治疗 为那些抵制传统习俗的人提供便利的方式 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.