GENETICS OF OSTEON REMODELING IN THE BABOON

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。重要性：这项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衰弱的疾病，通常会导致长期的活动能力丧失甚至死亡。骨的维持和修复的骨细胞重建过程是骨质疏松症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的遗传调节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。这项研究可能会产生新的有用信息，因为它是第一项正式测试遗传对骨重塑过程和结果的影响的研究。它正在使用目前唯一可以解决这个问题的骨骼收集进行（即，纯种个体）。基于骨生物学的其他研究，预期的结果是狒狒将是人类骨单位重塑过程的合适模型，骨单位形态和分布将显示出显着的遗传效应。 骨细胞重塑导致皮质骨中与年龄相关的微结构变化，从而增加骨质疏松性骨折的风险。对这一过程的遗传调控的理解将使早期识别那些个体的最大风险的皮质骨骨折，允许早期实施预防和治疗策略。我建议用灵长类动物模型来研究骨细胞重塑的遗传学。待检验的假设是：H1：狒狒提供了一个适当的模型，在人类的骨单位重塑过程中，表现出相似的骨单位形态，重塑动力学，年龄和性别的影响。H2：骨单位形态和重塑动力学在狒狒中是可遗传的。证明遗传性对于向美国国立卫生研究院申请额外资金以增加基因分型狒狒的样本进行全基因组连锁筛选以确定有助于皮质骨微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性别和年龄特异性遗传效应的研究。该试验项目的目的是：1）表征狒狒骨单位重塑动力学中的正常变化，包括年龄和性别效应，2）量化骨单位形态和重塑中归因于基因的变化比例。

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.