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Systems Genetics of Osteoblast Activity

成骨细胞活性的系统遗传学

基本信息

批准号：
9294972
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 40.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294972
关键词：
Affect Age Alpha Cell American Anabolic Agents Area BTB/POZ Domain Bioinformatics Biology Bone Density Bone Development Bone Diseases Bone Resorption Calvaria Candidate Disease Gene Cells Complex Data Development Disease Dissection Drug Targeting Economic Burden Ensure Environmental Risk Factor Fracture Genes Genetic Genetic study Goals Hereditary Disease Heritability Human Human Genetics Human Genome In Vitro Individual Laboratories Lead Maps Measures Mediating Medical Economics Methodology Minerals Mus Mutant Strains Mice Nodule Osteoblasts Osteoclasts Osteogenesis Osteoporosis Phenotype Physiological Pilot Projects Population Process Progressive Disease Protein Kinase Proteins Public Health Quantitative Trait Loci Regulation Research Resolution Risk Role Societies System Testing Therapeutic Time WNT4 gene Zinc Fingers base bone bone mass candidate validation common treatment fracture risk gene discovery genetic analysis genetic association genome wide association study genome-wide in vivo innovation knock-down new therapeutic target novel novel strategies osteoporosis with pathological fracture overexpression public health relevance success therapeutic target trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant) Osteoporosis is a disease of progressive bone loss, leading to weak and fracture prone bones. This disease affects ~12 million Americans and is a major medical and economic burden on society. Osteoporosis is primarily a genetic disorder with fracture-related traits, such as bone mineral density (BMD), being among the most highly heritable disease associated phenotypes. In humans and mice, genetic studies to date have focused almost exclusively on the analysis of BMD. However, BMD is a complex organismal-level trait that is influenced by a complicated milieu of genetic and environmental factors. This has hampered our ability to precisely identify the causal genes that underlie genetic associations. As an alternative, we propose to focus exclusively on the genetics of a more 'simple' cell-level process, osteoblast-mediated bone formation. The objective of this proposal is to identify genes affecting osteoblast function. This will be accomplished using a novel and innovative mouse genetic reference population termed the Collaborative Cross (CC). In a pilot study, we identified two genome-wide associations in the mouse for osteoblast activity and using bone expression and human GWAS we have identified three candidate genes potentially underlying these associations. In Aim 1, we will evaluate the effect of modulating expression levels of these candidates on osteoblast function in vitro. In Aim 2, we will map additional high-resolution quantitative trait loci (QTL) for mineralized nodule formation, a physiologically relevant measure of osteoblast-mediated bone formation, in the CC. In Aim 3, we will move from QTL to the identification and validation of candidate genes for mineralized nodule formation QTL. This will be accomplished by exploiting the unique genetic aspects of the CC to bioinformatically narrow these loci, followed by RNA-seq/expression QTL studies to further pinpoint causative genes. Candidate genes for mineralized nodule formation QTL will be tested by gene overexpression and knockdown and mutant mouse studies. We expect that the study of a cell-level process will provide the means to more efficiently go from locus to gene to mechanism. Genes that we identify will serve as potential therapeutic targets capable of increasing bone formation in the setting of osteoporosis.