Genetic Determinants of Bone Fragility

描述（由申请方提供）：与骨相关的骨质疏松性骨折主要是由于跌倒倾向增加和骨强度随年龄增长而降低导致的骨脆性增加。几个因素有助于骨强度，包括骨矿物质密度（BMD），骨结构和骨质量，所有这些都具有高度遗传的表型。在本奖项的任期内，我们已经确定了几个非常有前途的染色体区域，这些区域含有影响白色和黑人美国男性和女性以及大鼠峰值骨强度的基因。本申请的目的是进一步定义与峰值骨强度表型相关的QTL，鉴定哪些QTL是性别特异性的，并使用组合的位置克隆/候选基因方法鉴定骨脆性的基础基因。预计这些拟议的研究将大大有助于我们了解女性比男性和美国白人比黑人更高的骨质疏松性骨折风险的原因。此外，这些基因的鉴定可能：1）导致预测骨质疏松症风险的分子测试，从而允许早期预防措施的建立; 2）提供对骨脆性和骨折倾向的基础骨骼生物学的深入了解;和3）确定旨在增加骨强度的治疗剂开发的分子靶点。

DESCRIPTION (provided by applicant): Age-related osteoporotic fractures are largely due to an increased propensity to fall and an increase in bone fragility due to a reduction in bone strength with aging. Several factors contribute to bone strength including bone mineral density (BMD), bone structure, and bone quality, all of which have phenotypes that are highly heritable. During the tenure of the current award we have identified several highly promising chromosomal regions that contain genes that influence peak bone strength in white and black American men and women and in rats. The goal of this application is to further define QTL that are linked to phenotypes of peak bone strength, identify which QTL are sex-specific, and to identify genes that underlie bone fragility using the combined positional cloning/candidate gene approach. It is expected that these proposed studies will greatly contribute to our understanding of the reasons for the higher risk of osteoporotic fracture in women than men and in American whites than blacks. Furthermore, identification of these genes may: 1) lead to molecular tests that predict the risk of osteoporosis, thereby allowing the early institution of preventive measures; 2) provide insight into the basic skeletal biology that underlies bone fragility and the predisposition to fracture; and 3) identify molecular targets for the development of therapeutic agents aimed at increasing bone strength.