GENETIC AND DYNAMIC ANALYSIS OF MURINE BONE SIZE

小鼠骨大小的遗传和动态分析

• 批准号: 6375235
• 负责人: JON E. WERGEDAL
• 金额: $ 37.32万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375235
• 关键词: animal population genetics; body physical characteristic; bone; bone development; bone fracture; genetic susceptibility; inbreeding; insulinlike growth factor; laboratory mouse; linkage mapping; mechanical stress; periosteums; quantitative trait loci

The risk for osteoporotic fractures, a significant problem in the aging population, is inversely related not only to bone mass, but also to bone size. Engineering principles predict that bone size is an important determinant of bone strength. A primary determinant of bone size, and thus, bone strength, is the periosteal bone formation (PBF). There is now evidence that each of these three interrelated phenotypes are influenced by genetic factors. Our preliminary studies indicate that bone size is inherited as a polygenic trait. A powerful tool to investigate polygenic traits is the QTL mapping approach. pQCT analysis revealed that the RF/j and the NZB/BinJ strains differed by 40 percent in bone size with corresponding differences in bone strength and PBF. The goal of this application is to identify and elucidate the actions of gene(s) that determine bone size, strength and PBF. Because information about candidate genes, which may be obtained by determining the mechanism(s) leading to a given phenotype, is very helpful in identification of the specific gene, this application also intends to determine the mechanistic basis for the differences in bone size. Therefore, this application has two sets of specific aims. The first set of aims is: 1) to establish the optimum timing for expression of the bone size, strength, and PBF phenotypes in RFJ and NZB inbred strains of mice; 2) to apply QTL mapping analysis to the F2 progenies of RF/J-NZB strain pair to identify gene loci that simultaneously regulate femur bone size, bone strength, and PBF; 3) to establish genetic linkage of QTL to regions of specific chromosomes; and 4) to produce congenic strain progeny in order to fine map the location of the major common QTL genes regulating all three phenotypes. The second specific aim will determine the mechanism(s) leading to the greater bone size in the congenic strains of mice, by investigating two mechanisms which could regulate PBF: one deals with local mechanisms involving mechanical strain, and the other deals with systemic mechanisms involving systemic factors, such as serum IGF-I. If the hypothesis that genetically determined variations in PBF are a primary determinant of bone size and strength is correct, the genetic aspects of this work will reveal the chromosomal location for these genes that simultaneously control PBF, bone size and strength, and provides the framework for future work in determining the identity of these genes. The mechanistic studies with the congenic mice will yield important information on the mechanism whereby the gene understudy controls PBF, bone size and strength. Such a mechanism provides crucial information from both a biological and clinical standpoint with respect to bone fragility. Because the majority of the healing of a fracture takes place from the periosteum, it also seems likely that understanding the process of PBF could also help to understand fracture healing.

骨质疏松性骨折的风险是老龄化人口中的一个重要问题，它不仅与骨量成反比，还与骨大小成反比。 工程原理预测骨骼尺寸是骨骼强度的重要决定因素。 骨大小以及骨强度的主要决定因素是骨膜骨形成（PBF）。 现在有证据表明这三种相互关联的表型均受到遗传因素的影响。 我们的初步研究表明，骨骼大小是作为多基因性状遗传的。 QTL作图方法是研究多基因性状的有力工具。 pQCT 分析显示，RF/j 和 NZB/BinJ 菌株的骨大小相差 40%，骨强度和 PBF 也有相应的差异。 该应用的目标是识别和阐明决定骨骼大小、强度和骨密度的基因的作用。 由于关于候选基因的信息（可以通过确定导致给定表型的机制来获得）对于特定基因的识别非常有帮助，因此本申请还旨在确定骨大小差异的机制基础。 因此，该应用程序有两组具体目标。 第一组目标是： 1) 确定 RFJ 和 NZB 近交系小鼠中骨大小、强度和 PBF 表型表达的最佳时机； 2)对RF/J-NZB品系对的F2后代进行QTL作图分析，鉴定同时调节股骨大小、骨强度和PBF的基因位点； 3) 建立QTL与特定染色体区域的遗传连锁； 4) 产生同源品系后代，以便精细绘制调节所有三种表型的主要常见 QTL 基因的位置。 第二个具体目标是通过研究两种可以调节 PBF 的机制来确定导致同源品系小鼠骨尺寸增大的机制：一种涉及机械应变的局部机制，另一种涉及涉及全身因素（例如血清 IGF-I）的全身机制。 如果遗传决定的 PBF 变异是骨骼大小和强度的主要决定因素的假设是正确的，那么这项工作的遗传方面将揭示这些同时控制 PBF、骨骼大小和强度的基因的染色体位置，并为未来确定这些基因的身份的工作提供框架。 对同系小鼠的机制研究将产生有关基因候选控制 PBF、骨大小和强度的机制的重要信息。 这种机制从生物学和临床角度提供了有关骨脆性的重要信息。 由于骨折的大部分愈合发生在骨膜上，因此了解 PBF 的过程似乎也有助于了解骨折愈合。