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 相关复合物。这些复合物的成分在进化上是保守的，并且首先在酵母中被鉴定出来，它们是介导交配类型转换（SWI）的基因表达变化以及在没有葡萄糖的情况下转换为蔗糖利用的能力所必需的（蔗糖） -非发酵罐）。该复合物含有 DNA 依赖性 ATP 酶活性，为核小体重塑功能提供动力，从而允许转录因子进入启动子位点。酵母复合物一直是广泛遗传分析的目标，并且已经做了相当多的工作来解决酵母和哺乳动物复合物的核小体重塑机制，但令人惊讶的是，人们对复合物及其各个成分在分化中的生物学作用知之甚少。哺乳动物细胞。众所周知，复合物 ATP 酶活性的消除会阻碍一系列组织类型的正常分化功能。 ATP酶是复合物的分子马达，当然对其功能至关重要，但复合物含有七种或更多其他成分，这些成分被认为可以调节复合物的活性以响应特定信号，特别是响应激素。关于这些调节性非催化亚基的生物学作用的信息非常有限。阐明它们的作用将为了解复合物如何在精确调节的代谢过程中实现功能特异性提供急需的见解。因此，该项目建议开发分化模型，其中特定的复杂成分将在单个生物系统内单独耗尽。由此产生的表型将表明各个亚基的生物学作用。分化模型将在前成骨细胞系中开发，因为这些细胞对多种细胞外信号有反应，并且具有高度调节的顺序分化程序，该程序具有良好的特征并包括细胞周期调节。拟议的系统将提供与广泛的公共卫生问题相关的重要临床数据，例如骨质疏松症和炎症性疾病以及癌症。