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Co-localizing Quantitative Trait Loci for Bone Mineral Density and HDL in Mice

小鼠骨矿物质密度和 HDL 的定量性状基因座的共定位

基本信息

批准号：
8481189
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 29.5万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481189
关键词：
Affect Age Alleles American Bioinformatics Bone Density Boxing Candidate Disease Gene Cardiovascular Diseases Cause of Death Cholesterol Chromosome Mapping Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 8 Clinical Complex Congenic Mice Developed Countries Development Diagnosis Diet Dietary Cholesterol Disease Distal Eating Environment Environmental Risk Factor Exercise Fatty acid glycerol esters Genes Genetic Genetic Polymorphism Goals Haplotypes Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inbred Strains Mice Intake Integrin alpha Chains Knockout Mice Knowledge Lead Link Maps Measures Metabolism Modeling Mus Osteoblasts Osteoclasts Osteoporosis Patients Phenotype Physiology Quantitative Trait Loci Research Risk Risk Factors Serum Smoking Societies Techniques Testing adipocyte differentiation alanylaspartic acid aspartylglutamate bone bone morphogenic protein cardiovascular disorder risk disease diagnosis embryonic stem cell extracellular feeding glutamylalanine heart disease risk human GPT2 protein improved knockout gene lifestyle factors lipoprotein lipase novel osteoporosis with pathological fracture polypeptide prevent procollagen C-endopeptidase public health relevance trait

项目摘要

DESCRIPTION (provided by applicant): Half of all Americans either have or are at serious risk for developing osteoporosis. Bone mineral density (BMD) can be readily measured in a clinical setting, and low BMD is associated with increased risk of osteoporotic fracture. Cardiovascular disease (CVD) is a major cause of death in industrialized societies, and it is well established that raising HDL cholesterol reduces the risk of cardiovascular disease. Studies have shown that low BMD can be used as an independent predictor of CVD, and patients with CVD are more likely to have low BMD. Smoking, lack of exercise and eating a high fat "Western" diet increases the risk of developing both CVD and osteoporosis. Together these suggest that there may be shared causes for these two diseases. Both BMD and serum HDL levels have been shown to be genetically regulated. Preliminary studies in humans have suggested the existence of shared genetic causes for both of these phenotypes, but, as environmental and lifestyle factors influence both BMD and serum HDL levels, identifying the genetic link between CVD and osteoporosis has been difficult. The mouse is an excellent model for mapping genes that underlie complex traits, and, unlike in human studies, environment can be controlled and modulated as needed in studies using the mouse. Two quantitative trait loci (QTL) for BMD have been identified on mouse Chromosome 1 and 8 that are coincident for QTL for serum HDL. Furthermore, both of these BMD QTL interact with dietary cholesterol intake. The Chr 1 QTL has been narrowed down to one gene, and the Chr 8 QTL has been narrowed down to 4 candidate genes. In this application, a knockout mouse for the candidate gene on Chr 1 will be developed to confirm that: 1) this gene underlies the BMD QTL on Chr 1; 2) this QTL interacts with dietary cholesterol intake to affect BMD; and 3) this same gene regulates serum HDL levels. In the second Aim, the gene underlying the BMD QTL on Chr 8 will be identified, and the hypothesis that a single gene at this locus regulates both the BMD and HDL QTL will be confirmed.

描述(由申请人提供)：一半的美国人患有或面临严重的骨质疏松症风险。骨密度(BMD)很容易在临床环境中测量，低BMD与骨质疏松性骨折的风险增加有关。心血管疾病(CVD)是工业化社会的主要死亡原因，众所周知，提高高密度脂蛋白可降低心血管疾病的风险。研究表明，低骨密度可以作为心血管疾病的独立预测指标，而患有心血管疾病的患者更有可能出现低骨密度。吸烟、缺乏锻炼和吃高脂肪的西式饮食会增加患心血管疾病和骨质疏松症的风险。这些都表明，这两种疾病可能存在共同的原因。BMD和血清高密度脂蛋白水平都被证明是受基因控制的。在人类中的初步研究表明，这两种表型都存在共同的遗传原因，但由于环境和生活方式因素同时影响BMD和血清高密度脂蛋白水平，因此很难确定心血管疾病和骨质疏松症之间的遗传联系。老鼠是定位构成复杂特征的基因的极佳模型，而且与人类研究不同，环境可以在使用老鼠进行研究时根据需要进行控制和调节。在小鼠1号和8号染色体上发现了两个与血清高密度脂蛋白(HDLQTL)相一致的骨密度QTL。此外，这两个BMD QTL都与饮食中的胆固醇摄入量相互作用。Chr1 QTL已缩小到1个基因，Chr8 QTL已缩小到4个候选基因。在这个应用中，我们将建立一个针对Chr1候选基因的敲除小鼠，以确认：1)该基因位于Chr1上的BMD QTL之下；2)该QTL与饮食中的胆固醇摄入量相互作用以影响BMD；以及3)该基因调节血清高密度脂蛋白水平。在第二个目标中，将确定在Chr 8上的BMD QTL的潜在基因，并将证实该座位上的单个基因同时调节BMD和HDLQTL的假设。