GENETICS OF OSTEON REMODELING IN THE BABOON

狒狒骨重塑的遗传学

• 批准号: 7349832
• 负责人: LORENA M HAVILL
• 金额: $ 0.51万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349832
• 关键词: GENETICS; OSTEON; REMODELING; BABOON

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。意义：这项研究的重要性在于皮质骨微结构的各个方面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，通常会导致长期活动能力丧失甚至死亡。骨质维持和修复的骨性重塑过程是骨质疏松症发病机制的重要组成部分，也是与年龄相关的皮质骨丢失和微结构改变的原因。了解这一过程和由此产生的微观结构变化受到基因调控的程度，是提供一种机制以识别最有可能发生骨折的个人的关键的第一步，以便尽早开始疗程，从而提高其疗效。这项拟议的研究可能会产生新的有用信息，因为这是第一项正式测试遗传对骨重建过程和结果影响的研究。目前正在使用目前唯一可以解决这一问题的骨骼标本(即纯种个体)进行这项研究。基于骨生物学的其他研究，预期的结果是，狒狒将成为人类骨骼重塑过程的合适模型，骨细胞的形态和分布将显示出显著的遗传效应。骨质重塑导致皮质骨的微结构年龄相关变化，从而增加骨质疏松性骨折的风险。了解这一过程的遗传规律将有助于更早地识别皮质骨骨折风险最高的个体，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建的遗传学。需要检验的假设是：H1：狒狒为人类的骨重建过程提供了一个合适的模型，显示出相似的骨细胞形态、重建动力学以及年龄和性别效应。H2：在狒狒身上，骨的形态和重塑动力学是可遗传的。为了向美国国立卫生研究院申请额外资金，以增加基因分型的狒狒样本，进行全基因组连锁筛查，以确定导致皮质骨微结构正常变异的染色体区域和特定基因，证明遗传性是至关重要的。这些数据还将为未来性别和年龄特定的遗传效应的研究奠定基础。这个先导项目的目的是：1)表征正常变异，包括年龄和性别的影响，在狒狒的骨改建动力学，和2)量化的比例，骨形态变异和改建归因于基因。