Regulation of gene expression: biomolecular interactions in cellular development and disease

基因表达调控：细胞发育和疾病中的生物分子相互作用

• 批准号: nhmrc : 402762
• 负责人: Prof Jacqueline Matthews
• 金额: $ 199.95万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: Programs
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/regulation-gene-expression-development-disease/96714
• 关键词: Regulation; gene; expression; biomolecular; interactions

This team consists of three of Australia�s younger researchers Merlin Crossley, Joel Mackay and Jacqui Matthews (as Chief Investigators), who are recognized as authorities in the areas of gene regulation and the structural and functional analysis of proteins. They are joined by Mitchell Weiss, a world authority on blood development and clinical disorders,and Alexis Verger, a molecular and cell biologist recruited from France, both as Principal Investigators. Crossley, Mackay and Matthews have worked as a team for around six years to date, have published together in high-quality international journals, and have received anumber of accolades for their contributions to Australian science. For example, Crossley has won a number of national awards, including the Gottschalk Medal of the Australian Academy of Science; Mackay was recently awarded the Prime Minister�s Prize for Life Scientist of the Year, and Matthews won the only Charles and Sylvia Viertel Medical Research Fellowship to be awarded in 2003. The members of this team have collaborated extensively on the world stage and Crossley, Mackay and Matthews have also taken leadership roles in the Australian scientific community. Mitchell Weiss has been an important collaborator, exchanging reagents and advice, since he and Crossley trained together as postdocs in Stu Orkin�s lab at Harvard in the early 90s. Most recently Weiss, in collaboration with Mackay, has made important discoveries on a-globin production, which has led to several highly significant publications including a seminal paper in Cell in 2004.The program of research put forward in this proposal centres around understanding the mechanisms through which genes are switched on and off, using blood development as a model system, that is also fundamental to human life. The regulation of gene output is essential both during the development of an organism and throughout the course of its life. Problems with this regulation can result in many different disease states, most notably cancer, which includes the many different types of leukemias. At one level, gene output is controlled by networks of specific proteins known as transcription factors that interact both with each other and with DNA. Currently, however, the details surrounding which complexes regulate which genes and the processes that control the making and breaking up of the complexes are not well understood. Knowledge of how these interactions take place will put us in a position to control the output of chosen genes for therapeutic purposes. We propose to use a combination of cell biological, biochemical, and structural approaches to firstly shed light on these complexes and secondly develop reagents that can be used to manipulate the activity of specific genes.

该团队由三位澳大利亚年轻的研究人员Merlin Crossley，Joel Mackay和Jacqui马修斯（作为首席研究员）组成，他们被公认为基因调控和蛋白质结构和功能分析领域的权威。他们加入了米切尔韦斯，世界权威的血液发展和临床疾病，和亚历克西斯Verger，分子和细胞生物学家从法国招募，都作为首席研究员。到目前为止，克罗斯利、麦凯和马修斯作为一个团队工作了大约六年，他们一起在高质量的国际期刊上发表文章，并因对澳大利亚科学的贡献而获得了许多赞誉。例如，克罗斯利赢得了许多国家奖项，包括澳大利亚科学院的戈特沙尔克奖章;麦凯最近被授予总理年度生命科学家奖，马修斯赢得了2003年唯一的查尔斯和西尔维亚·维尔特尔医学研究奖学金。这个团队的成员在世界舞台上进行了广泛的合作，克罗斯利、麦凯和马修斯也在澳大利亚科学界发挥了领导作用。米切尔韦斯一直是一个重要的合作者，交换试剂和建议，因为他和克罗斯利一起训练作为博士后在斯图奥金的实验室在哈佛在90年代初。最近，韦斯与麦凯合作，在α-珠蛋白的生产方面取得了重要发现，这导致了几个非常重要的出版物，包括2004年在《细胞》上发表的一篇开创性论文。这项提议提出的研究计划围绕着理解基因开启和关闭的机制，使用血液发育作为模型系统，这也是人类生命的基础。基因输出的调节在生物体的发育和整个生命过程中都是必不可少的。这种调节的问题可能导致许多不同的疾病状态，最明显的是癌症，其中包括许多不同类型的白血病。在一个层面上，基因输出是由称为转录因子的特定蛋白质网络控制的，这些蛋白质相互作用并与DNA相互作用。然而，目前，围绕哪些复合物调节哪些基因以及控制复合物的制造和分解的过程的细节还没有很好地理解。了解这些相互作用是如何发生的，将使我们能够控制选定基因的输出，以达到治疗目的。我们建议使用细胞生物学，生物化学和结构方法的组合，首先阐明这些复合物，其次开发可用于操纵特定基因活性的试剂。