The epigenetic role of LSD1 in osteoclast differentiation

项目总结 骨质疏松症和牙周病等疾病每年影响美国数百万人 并在治疗上花费了数十亿美元。破骨细胞是一种大的多核细胞，分泌酸性物质和 蛋白水解酶转化为骨吸收。了解调控破骨细胞分化的分子机制 而活性将提供关于过度活跃的破骨细胞如何导致病理性骨丢失的洞察， 会导致骨质疏松症和牙周病。对DNA的可逆修饰，如组蛋白 乙酰化、甲基化、磷酸化和泛素化改变了转录机制对 DNA和调控基因表达。赖氨酸特异的脱甲基酶1(LSD1)，也被称为KDM1A，是第一个 特异性脱甲基组蛋白赖氨酸4的组蛋白去甲基酶 3(H3K4me1/2)或组蛋白3的赖氨酸9(H3K9me1/2)。LSD1通过以下方式给予转录抑制 去甲基化H3K4或通过去甲基化H3K9激活转录。LSD1的作用机制 调控破骨细胞基因的表达和分化目前尚不清楚。提供的初步数据 这一建议表明，抑制LSD1活性或表达会导致LSD1单甲基化增加 H3K4me1和破骨细胞分化增加。这些初步数据表明，LSD1是一种抑制因子 破骨细胞基因表达。这项建议旨在描述LSD1在调节破骨细胞中的作用 在动物模型和体外细胞培养模型中的分化(目标1)和鉴定 受LSD1调控的破骨细胞基因(目标2)。这些研究目标将通过 应用程序的培训目标。这些培训目标包括学习技术，如Micro-CT、RNA-SEQ 和CHIP-SEQ，以及参加期刊俱乐部和地方和国家科学会议。培训 在明尼苏达大学举行，该校为研究和研究提供了良好的环境 临床牙科培训。

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.