Genetic Determinants of Bone Fragility

描述(申请人提供)：与年龄相关的骨质疏松性骨折主要是由于跌倒的倾向增加，以及由于随着年龄的增长骨强度降低而增加的骨骼脆性。影响骨强度的因素包括骨密度(BMD)、骨结构和骨质量，所有这些因素都具有高度可遗传的表型。在当前奖项的任期内，我们已经确定了几个非常有希望的染色体区域，这些区域包含影响美国白人和黑人男性和女性以及老鼠的峰值骨强度的基因。这项应用的目标是进一步定义与骨峰值强度表型相关的QTL，识别哪些QTL是性别特异的，并使用位置克隆/候选基因相结合的方法识别导致骨骼脆性的基因。预计这些拟议的研究将极大地有助于我们理解女性比男性和美国白人比黑人患骨质疏松性骨折风险更高的原因。此外，对这些基因的识别可能：1)导致预测骨质疏松症风险的分子测试，从而使早期制定预防措施；2)提供对骨骼脆性和骨折易感性背后的基本骨骼生物学的洞察；以及3)为旨在增加骨骼强度的治疗剂的开发确定分子靶点。

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.