SWI/SNF-related complex in osteoblast differentiation

成骨细胞分化中 SWI/SNF 相关复合物

• 批准号: 7105890
• 负责人: Elizabeth Moran
• 金额: $ 28.52万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105890
• 关键词: RNA interference; adenosinetriphosphatase; cell differentiation; cell growth regulation; cell line; enzyme activity; gene expression; gene targeting; genetic models; laboratory mouse; laboratory rat; osteoblasts; phenotype; protein structure; protein structure function; small interfering RNA; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Mammalian SWI/SNF-related complexes are required for tissue specific gene expression. The components of these complexes are evolutionarily conserved, and were first identified in yeast, where they are required for the changes in gene expression that mediate the mating type switch (SWI) and the ability to switch to sucrose utilization in the absence of glucose (Sucrose-Non-Fermentors). The complexes contain a DNA-dependent ATPase activity that powers a nucleosome remodeling function, which in turn allows transcription factor access to promoter sites. The yeast complexes have been the target of extensive genetic analysis, and considerable work has been done to address the mechanisms of nucleosome remodeling by yeast and mammalian complexes, but surprisingly little is known about the biological role of the complex and its individual components in the differentiation of mammalian cells. What is known is that abrogation of the ATPase activity of the complex blocks normal differentiation function in a range of tissue types. The ATPase is the molecular motor of the complex and is, of course essential to its function, but the complexes contain seven or more other components that are believed to modulate the activity of the complex in response to specific signals, particularly in response to hormones. Very limited information is available on the biological role of these modulatory, non-catalytic, subunits. Elucidation of their roles would give much-needed insight into how the complexes achieve specificity of function in precisely regulated metabolic processes. This project therefore proposes the development of differentiation models in which specific complex components will be depleted individually within a single biological system. The resulting phenotypes will indicate the biological roles of the individual subunits. The differentiation models will be developed in a pre-osteoblast line because these cells are responsive to multiple extracellular signals and have a highly regulated and sequential differentiation program that is well-characterized and includes cell cycle regulation. The proposed systems will provide important clinical data, relevant to broad public health problems, such as osteoporosis and inflammatory diseases, as well as to cancer.

描述（由申请人提供）：组织特异性基因表达需要哺乳动物SWI/SNF相关的复合物。这些配合物的成分在进化上是保守的，并首先在酵母中鉴定出来，在酵母中介导了介导交配类型开关（SWI）的基因表达的变化，并且在没有葡萄糖（蔗糖 - 非侵害者）的情况下可以切换到蔗糖利用的能力。复合物包含DNA依赖性ATPase活性，该活性为核小体重塑函数提供动力，进而使转录因子访问启动子位点。酵母菌络合物一直是广泛的遗传分析的目标，并且已经完成了相当大的工作来解决酵母和哺乳动物络合物的核小体重塑的机制，但令人惊讶的是，关于该络合物的生物学作用及其各个成分在哺乳动物细胞区分中的生物学作用知之甚少。众所周知，复合物的ATPase活性废除了一系列组织类型中的正常分化函数。 ATPase是复合物的分子运动，当然对于其功能至关重要，但是络合物包含七个或更多其他成分，这些组件被认为可以根据特定信号调节复合物的活性，尤其是对激素的响应。有关这些调节性，非催化，亚基的生物学作用的信息非常有限。阐明它们的作用将使人们对复合物如何在精确调节的代谢过程中获得功能的特异性具有急需的见解。因此，该项目提出了分化模型的开发，其中特定的复杂成分将在单个生物系统中单独耗尽。由此产生的表型将指示各个亚基的生物学作用。分化模型将在骨细胞前系中开发，因为这些细胞对多个细胞外信号有反应，并且具有高度调节和顺序的分化程序，该程序已良好，包括细胞周期调节。所提出的系统将提供重要的临床数据，这些数据与广泛的公共卫生问题有关，例如骨质疏松和炎症性疾病以及癌症。