Effect of Gli2 on BMP-2 gene expression & bone formation

Gli2对BMP-2基因表达的影响

• 批准号: 7059479
• 负责人: MING ZHAO
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059479
• 关键词: acid aminoacid ligase; bone morphogenetic proteins; cell differentiation; genetic transcription; genetically modified animals; laboratory mouse; osteoblasts; osteogenesis; transcription factor; ubiquitin

DESCRIPTION (provided by applicant): Bone morphogenetic protein-2 (BMP-2) is important in the control of both skeletal morphogenesis and postnatal bone formation. However, little is known of the factors that regulate BMP-2 expression. Therefore, there is a great need to identify molecular mechanisms that are involved in the regulation of BMP-2 gene expression in osteogenesis, which serves as the short term goal of the candidate. The immediate objective of this proposal is to test the hypothesis that the zinc finger protein Gli2 influences bone formation by its regulatory effects on BMP-2 expression. The candidate's long-term goal is to develop an independent research career and to establish a solid multi-funded program on the studies of molecular mechanisms underlying the activation of bone formation, specifically focusing on bone anabolic signaling and gene regulation. The candidate will use this K01 to acquire additional skills in bone molecular biology. The mentors, Dr. Mundy and Dr. Harris, renowned experts in the field of bone biology, will provide excellent training experience for the candidate in "state of the art" institutional facilities at UTHSC at San Antonio. During phase I of the award, the candidate will benefit from the scientific guidance of two mentors. By phase II, the candidate will become a fully independent investigator. Genetic studies have shown that disruption of transcription factor GN2 results in severe bone defects, and our preliminary data suggests that GH2 up-regulates BMP-2 gene transcription. The proposed studies seek to confirm these preliminary observations, and to elucidate the mechanisms mediating the effect of GH2 on BMP-2 expression as well as on subsequent osteoblast differentiation and bone formation. Four specific aims are proposed (1) to determine the effects of loss-of-function of GH2 on osteoblast differentiation and BMP-2 gene expression, (2) to determine the molecular mechanisms by which Gli2 transactivates BMP-2 gene, (3) to examine the effects of overexpression of GH2 on bone formation in vivo in Gli2 transgenic mice and (4) to investigate the effects of the E3 ubiquitin ligase beta-TrCP on GH2 processing in osteoblasts. Full characterization of the roles of Gli2 protein in the regulation of BMP-2 gene expression and skeletogenesis should lead to insights into the molecular mechanisms of bone anabolic regulation.

描述（由申请人提供）：骨形态发生蛋白-2（BMP-2）在控制骨骼形态发生和出生后骨形成方面很重要。然而，很少有人知道的因素，调节BMP-2的表达。因此，非常需要鉴定参与骨生成中BMP-2基因表达调控的分子机制，这是候选人的短期目标。该建议的直接目标是测试锌指蛋白Gli 2通过其对BMP-2表达的调节作用影响骨形成的假设。候选人的长期目标是发展独立的研究事业，并建立一个坚实的多基金项目，研究骨形成激活的分子机制，特别关注骨合成代谢信号传导和基因调控。候选人将使用此K 01获得骨分子生物学的额外技能。导师Mundy博士和Harris博士是骨生物学领域的著名专家，他们将在圣安东尼奥UTHSC的“最先进”机构设施中为候选人提供出色的培训经验。在该奖项的第一阶段，候选人将受益于两位导师的科学指导。到第二阶段，候选人将成为完全独立的调查员。遗传学研究表明，转录因子GN 2的破坏导致严重的骨缺损，我们的初步数据表明，GH 2上调BMP-2基因转录。拟议的研究试图证实这些初步观察结果，并阐明GH 2对BMP-2表达以及随后的成骨细胞分化和骨形成的介导作用的机制。本研究提出了四个具体目标：（1）确定GH 2功能缺失对成骨细胞分化和BMP-2基因表达的影响，（2）确定Gli 2反式激活BMP-2基因的分子机制，（3）检查GH 2过表达对Gli 2转基因小鼠体内骨形成的影响，以及（4）研究E3泛素连接酶β-TrCP对成骨细胞中GH 2加工的影响。充分表征Gli 2蛋白在BMP-2基因表达和骨骼发生调控中的作用，将有助于深入了解骨合成代谢调控的分子机制。