GENETIC AND DYNAMIC ANALYSIS OF MURINE BONE SIZE

小鼠骨大小的遗传和动态分析

• 批准号: 6127845
• 负责人: JON E. WERGEDAL
• 金额: $ 37.14万
• 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/6127845
• 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年人群中的一个重要问题，不仅与骨量呈负相关，而且与骨大小呈负相关。 工程学原理预测，骨大小是骨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中的每一种都受到遗传因素的影响。 我们的初步研究表明，骨骼大小是作为一个多基因性状遗传。 QTL定位是研究多基因性状的有力工具。 pQCT分析显示，RF/j和NZB/BinJ菌株在骨大小上相差40%，在骨强度和PBF上也有相应的差异。 本申请的目的是鉴定和阐明决定骨大小、强度和PBF的基因的作用。 因为通过确定导致给定表型的机制可以获得的关于候选基因的信息对于鉴定特定基因非常有帮助，所以本申请还旨在确定骨大小差异的机制基础。 因此，本申请有两套具体目标。 第一组目标是：1）确定RFJ和NZB近交系小鼠骨大小、骨强度和PBF表型表达的最佳时间; 2）对RF/J-NZB品系对的F2后代应用QTL定位分析以鉴定同时调节股骨骨大小、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）产生同源株系后代，以精细定位调控所有三种表型的主要共有QTL基因。 第二个具体目标将通过研究可以调节PBF的两种机制来确定导致同类系小鼠中更大骨尺寸的机制：一种涉及涉及机械应变的局部机制，另一种涉及涉及全身因素（如血清IGF-I）的全身机制。 如果遗传决定的PBF变异是骨大小和强度的主要决定因素的假设是正确的，这项工作的遗传方面将揭示这些基因的染色体位置，同时控制PBF，骨大小和强度，并提供了框架，为未来的工作，在确定这些基因的身份。 同系小鼠的机制研究将产生重要的信息的机制，即该基因的候补控制PBF，骨大小和强度。 这种机制提供了关于骨脆性的生物学和临床观点的关键信息。 由于骨折的愈合大多发生在骨膜，因此了解PBF的过程也可能有助于理解骨折愈合。