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

该团队由三名澳大利亚�S年轻研究员Merlin Crossley、Joel Mackay和Jacqui Matthews(首席研究员)组成，他们是基因调控和蛋白质结构和功能分析领域的公认权威。血液发育和临床疾病方面的世界权威Mitchell Weiss和从法国招聘的分子和细胞生物学家Alexis Verger也加入了他们的行列，他们都是首席研究员。到目前为止，克罗斯利、麦凯和马修斯作为一个团队已经工作了大约六年，他们一起在高质量的国际期刊上发表了文章，并因他们对澳大利亚科学的贡献而获得了许多赞誉。例如，克罗斯利获得了多个国家奖项，包括澳大利亚科学院戈特沙尔克奖章；麦凯最近被授予总理�S年度生命科学家奖；马修斯获得了2003年唯一颁发的查尔斯和西尔维娅·维耶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。自从90年代初米切尔·韦斯和克罗斯利作为博士后一起在哈佛大学的斯图奥尔金�S实验室接受博士后培训以来，米切尔·韦斯一直是一个重要的合作者，交换试剂和建议。最近，韦斯与麦凯合作，在α-珠蛋白生产方面取得了重要发现，这导致了几篇非常重要的论文，包括2004年发表在《细胞》杂志上的一篇开创性论文。这项提案中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。这一规定的问题可能会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，基因输出由被称为转录因子的特定蛋白质网络控制，这些蛋白质相互作用，也与DNA相互作用。然而，目前关于哪些复合体调节哪些基因以及控制复合体的形成和分解的过程的细节还不是很清楚。了解这些相互作用是如何发生的，将使我们能够控制用于治疗目的的选定基因的输出。我们建议使用细胞生物学、生化和结构方法的组合来首先阐明这些复合体，然后开发可以用来操纵特定基因活性的试剂。

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.