The Role of AML1 in Osteoclastogenesis and Osteoclast Gene Expression

AML1 在破骨细胞生成和破骨细胞基因表达中的作用

• 批准号: 8247620
• 负责人: YI-PING LI
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247620
• 关键词: Role; AML1; Osteoclastogenesis; Osteoclast; Gene

The overall goal of this study is to understand the mechanism underlying transcription factors specifying osteoclast lineage commitment and differentiation. This proposal is highly significant since elucidating osteoclast lineage commitment and differentiation has potential to define new therapeutic targets for bone disorders that involve osteoclast generation and activation. Despite the recent insights gained from the effects of targeted deletion of the c-fos, PU.1, NF-¿B, and NFATc1 transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lino define new therapeutic targets for bone disorders that involve osteoclast generation and activation. Despite the recent insights gained from the effects of targeted deletion of the c-fos, PU.1, NF-¿monstrated that AML1 is highly induced by RANKL and M-CSF together. AML1 knockdown in mouse bone marrow culture induced by RANKL and M-CSF blocked osteoclast differentiation, but did not inhibit macrophage differentiation. However, AML1-/- liver cells failed to develop both monocytes/macrophages and osteoclasts. Our results showed that that AML1 may control osteoclast cell lineage commitment and regulate osteoclast gene expression and differentiation through upregulating PU.1 and NFATc1. Based on our Preliminary study, we hypothesize that AML1 is a key regulator that specifies osteoclast cell lineage commitment and differentiation at the transcriptional regulation level. We will test this hypothesis through two specific aims. We will define the functional role of AML1 in osteoclast cell lineage commitment and differentiation using RNAi knockdown and overexpression in Aim 1. We will investigate the role of AML1 in osteoclast differentiation in adult mice through bone tissue-specific targeted disruption of AML using a conditional knockout approach by Cre/loxP technology and characterize the phenotypes and pathomechanism of the AML1 conditional knockout mice. Ultimately, this knowledge will help to establish the roles of AML1 in osteoclast cell lineage commitment and differentiation. Thus, it will improve our understanding of osteolytic diseases and help to design novel approaches for the treatment of diseases such as osteoporosis, arthritis, periodontal disease, and bone metastases using drug or somatic gene therapy.

本研究的总体目标是了解转录因子指定的机制， 破骨细胞谱系定型和分化。这一建议意义重大，因为阐明了 破骨细胞谱系定型和分化有可能定义新的骨治疗靶点 涉及破骨细胞生成和激活的疾病。尽管最近从这些影响中获得的见解 c-fos、PU.1、NF-B和NFATc 1转录因子基因的靶向缺失，作为转录因子指定破骨细胞（OC）lino的基础的机制为涉及破骨细胞生成和活化的骨疾病定义了新的治疗靶点。尽管最近从靶向删除c-fos、PU.1、NF-κ B的作用中获得的见解表明，AML 1是由RANKL和M-CSF共同高度诱导的。RANKL和M-CSF诱导的小鼠骨髓培养物中AML 1敲低阻断破骨细胞分化，但不抑制巨噬细胞分化。然而，AML 1-/-肝细胞未能开发单核细胞/巨噬细胞和破骨细胞。我们的研究结果表明，AML 1可能通过上调PU.1和NFATc 1来控制破骨细胞的谱系定型，并调节破骨细胞基因的表达和分化。基于我们的初步研究，我们假设AML 1是一个关键的调节器，指定破骨细胞谱系的承诺和分化在转录调控水平。我们将通过两个具体目标来检验这一假设。我们将使用Aim 1中的RNAi敲低和过表达来确定AML 1在破骨细胞谱系定型和分化中的功能作用。我们将研究AML 1在成年小鼠破骨细胞分化中的作用，通过骨组织特异性靶向破坏AML，使用条件性敲除方法通过Cre/loxP技术和表征AML 1条件性敲除小鼠的表型和病理机制。最终，这些知识将有助于确定AML 1在破骨细胞谱系定型和分化中的作用。因此，它将提高我们对溶骨性疾病的理解，并有助于设计新的方法来治疗疾病，如骨质疏松症，关节炎，牙周病和骨转移，使用药物或体细胞基因治疗。