The epigenetic role of LSD1 in osteoclast differentiation

LSD1在破骨细胞分化中的表观遗传作用

基本信息

批准号：
10268202
负责人：
KRISTINA ASTLEFORD-HOPPER
金额：
$ 4.33万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-29 至 2024-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268202
关键词：
Acetylation Acids Adult Affect American Animal Model Arthritis Bone Resorption Cell Culture Techniques Cell Differentiation process Cells ChIP-seq Chemicals Clinical Clinical Management Cues DNA Data Defect Dental Dental Care Development Disease Environment Epigenetic Process Excision Extracellular Matrix Fracture Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Transcription Goals Grant Growth Health Care Costs Histone Acetylation Histone Deacetylase Histones Hyperactivity In Vitro Individual Journals KDM1A gene Knowledge Lead Learning Lysine Maintenance Malignant Neoplasms Methylation Minerals Minnesota Modeling Modification Molecular Morbidity - disease rate Multipotent Stem Cells Osteoclasts Osteogenesis Osteolytic Osteoporosis Pathologic Pathology Patients Peptide Hydrolases Periodontal Diseases Periodontitis Pharmacologic Substance Phenotype Phosphorylation Physiology Play Proteins Public Health Regulator Genes Research Role Skeleton Techniques Testing Tissues Tooth Loss Training United States Universities age related bone bone loss care costs cell type cost demethylation drug development experimental study gene repression genetic corepressor histone demethylase histone modification inhibitor/antagonist innovation insight meetings member methyl group microCT mouse model novel prevent repaired skeletal skeletal disorder small hairpin RNA targeted treatment transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Diseases such as osteoporosis and periodontal disease affect millions of individuals annually in the United States and cost billions in treatment. Osteoclasts are large, multinucleated cells that secrete acid and proteases to resorb bone. Understanding the molecular mechanisms that regulate osteoclast differentiation and activity will provide insight as to how the hyper-active osteoclasts causing pathological bone loss, contributes to osteoporosis and periodontal disease. Reversible modifications to DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alter the access of transcriptional machinery to DNA and regulate gene expression. Lysine-specific demethylase 1 (LSD1), also known as KDM1A, is the first identified histone demethylase capable of specially demethylating mono- and di-methylated lysine 4 of histone 3 (H3K4me1/2) or lysine 9 of histone 3 (H3K9me1/2). LSD1 confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9. The mechanism by which LSD1 regulates osteoclast gene expression and differentiation is currently unknown. Preliminary data presented in this proposal demonstrate inhibition of LSD1 activity or expression leads to an increase in mono-methylation of H3K4me1 and an increase in osteoclast differentiation. These preliminary data suggest LSD1 is a repressor of osteoclast gene expression. This proposal aims to characterize the role of LSD1 in regulating osteoclast differentiation in both an animal model and as well as in an in vitro cell culture model (Aim 1) and identifying the osteoclast genes that are regulated by LSD1 (Aim 2). These research goals will be enhanced by the training goals of the application. These training goals include learning techniques such as micro-CT, RNA-SEQ and ChIP-SEQ as well as participation in journal clubs and local and national scientific meetings. Training takes place at the University of Minnesota which offers an outstanding environment for both research and clinical dental training.

项目摘要骨质疏松症和牙周疾病等疾病每年会影响数百万个人国家和成本数十亿的治疗。破骨细胞是大的多核细胞，分泌酸，并且蛋白酶吸收骨骼。了解调节破骨细胞分化的分子机制活动将提供有关如何导致病理骨质流失的过度活跃破骨细胞的见解有助于骨质疏松症和牙周疾病。对DNA（例如组蛋白）的可逆修改乙酰化，甲基化，磷酸化和泛素化改变了转录机械对 DNA并调节基因表达。赖氨酸特异性脱甲基酶1（LSD1），也称为KDM1A，是第一个鉴定的组蛋白脱甲基酶，能够特殊脱甲基化的单甲基和二甲基化的组蛋白4 3（H3K4ME1/2）或组蛋白3（H3K9ME1/2）的赖氨酸9。 LSD1通过脱甲基H3K4或通过脱甲基H3K9激活转录。 LSD1的机制当前未知的骨细胞基因表达和分化。初步数据在该建议表明抑制LSD1活性或表达导致单甲基化的增加 H3K4ME1和破骨细胞分化的增加。这些初步数据表明LSD1是破骨细胞基因表达。该建议旨在表征LSD1在调节破骨细胞中的作用动物模型以及体外细胞培养模型（AIM 1）的分化并确定由LSD1调节的破骨细胞基因（AIM 2）。这些研究目标将由培训应用程序的目标。这些培训目标包括学习技术，例如Micro-CT，RNA-Seq 以及Chip-seq以及参与期刊俱乐部以及本地和国家科学会议。训练在明尼苏达大学举行，为研究提供了一个杰出的环境临床牙科训练。