Cardiac Gene Expression:Trascriptional Coactivators

心脏基因表达：转录共激活因子

• 批准号: 7014814
• 负责人: ERIC N Olson
• 金额: $ 61.41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014814
• 关键词: DNA binding protein; biological signal transduction; calcium binding protein; calcium flux; cardiogenesis; congenital heart disorder; developmental genetics; gene expression; gene induction /repression; gene targeting; genetic regulation; genetic screening; genetic transcription; genetically modified animals; heart; heart enlargement; heart function; human genetic material tag; human tissue; laboratory mouse; molecular cloning; myogenesis; protein structure function; striated muscles; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Abnormalities in heart development result in congenital heart disease, the most frequent form of birth defects in humans. It has been estimated that nearly 1% of newborns are affected by a congenital cardiac defect. At the opposite end of the temporal spectrum, adult cardiac disease is the most common cause of death in the industrialized world. Thus, there is a major need for the development of new approaches for prevention, genetic diagnosis and treatments of cardiovascular disorders, which requires a detailed understanding of the underlying mechanisms. Numerous transcription factors have been implicated in cardiac myogenesis and morphogenesis, but much remains to be learned about the mechanisms of cardiac gene regulation. The activities of transcription factors are dependent on their association with transcriptional coactivators and corepressors, many of which are signal-responsive and cell type-restricted. The modulation of transcription factor activity by association with coactivators and corepressors allows the integration of multiple regulators and provides for specialized control of different transcriptional programs. In an effort to fully understand the molecular basis of cardiac gene expression, we have devised eukaryotic expression screens for coactivators and corepressors of cardiac transcription factors. Such screens have led to the discovery of a novel and highly potent coactivator of the cardiac homeodomain protein Nkx2.5. This coactivator translocates to the nucleus in response to specific calcium-dependent signals and cooperates with Nkx2.5 to activate cardiac target genes. Similarly, a coactivator of the T-box protein Tbx5, which enhances the transcriptional activity of Tbx5 by several orders of magnitude, has been identified. The long-term goals of this project are to understand the mechanism of action of these and other coactivators and to define their functions in the control of cardiac gene expression during development and disease. We will use a combination of biochemical, cell biological and genetic approaches in cultured cells and in mice to achieve these goals. The results of this project will provide a detailed understanding of the mechanisms involved in normal and abnormal cardiac gene expression and will have implications for many aspects of cardiac function and dysfunction during development and adulthood.

描述（由申请人提供）：心脏发育异常会导致先天性心脏病，这是人类最常见的出生缺陷形式。据估计，近 1% 的新生儿患有先天性心脏缺陷。在时间谱的另一端，成人心脏病是工业化世界最常见的死亡原因。因此，迫切需要开发预防、基因诊断和治疗心血管疾病的新方法，这需要详细了解其潜在机制。许多转录因子与心肌发生和形态发生有关，但关于心脏基因调控的机制还有很多东西有待了解。转录因子的活性取决于它们与转录共激活子和辅阻遏物的关联，其中许多是信号响应性的且受细胞类型限制。通过与共激活子和辅阻遏物结合来调节转录因子活性，可以整合多个调节子，并提供对不同转录程序的专门控制。为了充分了解心脏基因表达的分子基础，我们设计了心脏转录因子的共激活子和辅阻遏物的真核表达筛选。这样的筛选导致了一种新型且高效的心脏同源结构域蛋白 Nkx2.5 共激活剂的发现。该共激活因子响应特定的钙依赖性信号转位至细胞核，并与 Nkx2.5 配合激活心脏靶基因。同样，T-box 蛋白 Tbx5 的共激活因子也已被鉴定，它可以将 Tbx5 的转录活性增强几个数量级。该项目的长期目标是了解这些和其他共激活剂的作用机制，并确定它们在发育和疾病期间控制心脏基因表达的功能。我们将在培养细胞和小鼠中结合使用生化、细胞生物学和遗传学方法来实现这些目标。该项目的结果将提供对正常和异常心脏基因表达所涉及的机制的详细了解，并将对发育和成年期间心脏功能和功能障碍的许多方面产生影响。