GENETICS OF OSTEON REMODELING IN THE BABOON

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。意义：本研究的重要性在于皮质骨微观结构与股骨颈骨折风险增加之间的联系，股骨颈骨折是一种特别虚弱的疾病，经常导致长期活动能力丧失甚至死亡。骨维持和修复的骨重塑过程是骨质疏松发病机制的重要组成部分，并负责与年龄相关的皮质骨丢失和微结构变化。了解这一过程和由此产生的微观结构变化受基因调控的程度是提供一种机制来识别骨折风险最大的个体的重要的第一步，这样治疗过程就可以尽早开始，从而提高疗效。这项拟议的研究可能会产生新的有用的信息，因为它是第一个正式测试骨重塑过程和结果的遗传影响的研究。它正在使用目前唯一可用的骨骼收集来处理这个问题（即，纯种个体）。基于其他骨生物学研究的预期结果是，狒狒将成为人类骨重塑过程的合适模型，骨的形态和分布将显示出显著的遗传效应。骨重塑导致皮质骨微结构年龄相关变化，增加骨质疏松性骨折的风险。了解这一过程的遗传调控将有助于更早地识别皮质骨骨折风险最大的个体，从而更早地实施预防和治疗策略。我建议使用灵长类动物模型来研究骨重塑的遗传学。有待验证的假设有：H1：狒狒为人类的骨重塑过程提供了合适的模型，表现出相似的骨形态、重塑动力学以及年龄和性别影响。H2：狒狒的骨细胞形态和重塑动力学是可遗传的。证明遗传能力对于向美国国立卫生研究院申请额外资金以增加基因型狒狒样本进行全基因组连锁筛选以确定导致皮质骨微观结构正常变异的染色体区域和特定基因至关重要。这些数据也将支持未来对特定性别和年龄的基因影响的研究。该试点项目的目的是：1)表征狒狒骨细胞重塑动力学中的正常变异，包括年龄和性别影响；2)量化可归因于基因的骨细胞形态和重塑的变异比例。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Significance: The importance of this research lies in the link between aspects of cortical bone microstructure and increased risk of femoral neck fracture, a particularly debilitating condition that often results in long term mobility loss and even mortality. The osteonal remodeling process of bone maintenance and repair is an essential component of osteoporosis pathogenesis and is responsible for age-associated cortical bone loss and microstructural changes. Understanding the degree to which this process and the resulting microstructural changes are genetically regulated is an essential first step in providing a mechanism to identify individuals at greatest risk for fracture, so that courses of treatment can begin as early as possible, thereby increasing their efficacy. The proposed research is likely to produce new and useful information because it is the first study to formally test for genetic effects on the osteonal remodeling process and outcomes. It is being conducted using the only skeletal collection currently available in which this question can be addressed (i.e., pedigreed individuals). The expected result, based on other studies of bone biology, is that the baboon will be an appropriate model for the osteonal remodeling process in humans, and osteon morphology and distribution will show significant genetic effects. Osteonal remodeling results in microstructural age-related changes in cortical bone that contribute to risk of osteoporotic fracture. An understanding of the genetic regulation of this process will enable earlier identification of those individuals at greatest risk for cortical bone fracture, allowing for earlier implementation of prevention and treatment strategies. I propose to investigate the genetics of osteonal remodeling using a primate model. The hypotheses to be tested are: H1: The baboon provides an appropriate model for the osteonal remodeling process in humans, showing similar osteon morphology, remodeling dynamics, and age and sex effects. H2: Osteon morphology and remodeling dynamics are heritable in the baboon. Demonstrating heritability is essential for application to the National Institutes of Health for additional funding to increase the sample of genotyped baboons to conduct genome-wide linkage screens to identify the chromosomal regions and specific genes that contribute to normal variation in cortical bone microstructure. These data will also underpin future investigations of sex- and age-specific genetic effects. The aims of this pilot project are to: 1) characterize normal variation, including age and sex effects, in osteon remodeling dynamics in the baboon, and 2) quantify the proportion of variation in osteon morphology and remodeling attributable in genes.