Gli2 on BMP-2 expression & bone formation in aging

Gli2 对 BMP-2 表达的影响

• 批准号: 6952325
• 负责人: MING ZHAO
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952325
• 关键词: RNA interference; aging; bone density; bone morphogenetic proteins; cell differentiation; gel mobility shift assay; gene expression; genetic regulation; genetically modified animals; intermolecular interaction; laboratory mouse; molecular biology; morphometry; organ culture; osteoblasts; osteogenesis; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Specific Topic: #20. Basic Underlying Mechanisms of Musculoskeletal Aging Skeletal aging is characterized by bone loss resulting in high risk of fracture in osteoporosis patients. The mechanisms for skeletal aging are not entirely clear, but likely relate to decreased availability of bone growth factors. Recent human genetic study demonstrated that osteoporosis is associated with the polymorphisms of BMP-2 gene. Animal studies have also indicated that an age-related decline of BMP-2 expression and function may account for one of the molecular pathogenic mechanisms of age-related osteopenia. But, how BMP-2 gene expression is regulated, especially in skeletal aging, is not well understood. Recent genetic studies have shown that the transcription factor Gli2 in Shh signaling pathway plays important roles in skeletal development. In our preliminary studies, we have found that Gli2 has dramatic stimulating effects on BMP-2 gene expression and osteoblast differentiation. Our hypothesis is that Gli2 is a powerful regulator for the BMP-2 gene expression and consequent postnatal bone formation, and plays important roles in skeletal aging. This proposal will identify the molecular mechanisms by which Gli2 stimulates BMP-2 gene expression and characterize the age-related effects of Gli2 on the regulation of BMP-2 expression and consequent bone formation. Two specific aims are proposed. First, we will explore the molecular mechanisms of Gli2 transactivation on BMP-2 gene by loss-of-function studies and the protein/DNA interaction. Secondly, we will determine the roles of Gli2 in age-related BMP-2 regulation and skeletal aging through characterizing tissue specific Gli2 transgenic mice. We believe that full characterization of the roles of Gli2 in BMP-2 gene regulation and postnatal bone formation will lead to insights into the molecular mechanisms of bone anabolic regulation especially in age-related bone biology, and provide a potential target for the treatment of clinical senile ostoepenia.

描述（由申请人提供）：特定主题：#20。肌肉骨骼老化的基本机制 骨老化的特征是骨质流失，导致骨质疏松症患者骨折的风险很高。骨骼衰老的机制尚不完全清楚，但可能与骨生长因子的可用性降低有关。近年来的人类遗传学研究表明，骨质疏松症与BMP-2基因多态性有关。动物研究也表明，与年龄相关的BMP-2表达和功能的下降可能是年龄相关性骨质减少的分子致病机制之一。但是，BMP-2基因表达是如何调节的，特别是在骨骼衰老中，还没有很好的了解。最近的遗传学研究表明Shh信号通路中的转录因子Gli 2在骨骼发育中起重要作用。在我们的初步研究中，我们发现Gli 2对BMP-2基因表达和成骨细胞分化具有显著的刺激作用。我们的假设是，Gli 2是一个强大的调节BMP-2基因的表达和随后的出生后骨形成，并在骨骼衰老中发挥重要作用。该提案将确定Gli 2刺激BMP-2基因表达的分子机制，并表征Gli 2对BMP-2表达和随后骨形成的调节的年龄相关效应。提出了两个具体目标。首先，我们将通过BMP-2基因的功能缺失和蛋白质/DNA相互作用来探讨Gli 2反式激活BMP-2基因的分子机制。其次，我们将通过组织特异性Gli 2转基因小鼠的特征来确定Gli 2在年龄相关的BMP-2调节和骨骼衰老中的作用。我们相信，充分表征Gli 2在BMP-2基因调控和出生后骨形成中的作用，将有助于深入了解骨合成代谢调控的分子机制，特别是与年龄相关的骨生物学，并为临床老年性骨质疏松症的治疗提供潜在的靶点。