CREB-Binding Protein (CBP)and Chromatin Remodeling

描述(由申请人提供)： 几乎任何疾病过程的病理生理学都可以用以下术语来描述 对基因产品的不当监管。DNA的构象影响 细胞？获取和利用基因的能力，以及改变基因的过程 染色质结构(染色质重塑)可能在 基因表达的控制。CREB结合蛋白(CBP)是一个重要的调节因子 许多基因的表达，我们的实验室已经证明 CBP通过乙酰化修饰其他蛋白质的能力对 此函数。我们还证明了CPB在染色质中是重要的 重建，但仍不清楚它是如何做到的，以及它的因素是什么 在染色质水平上与相互作用。解决这些问题是主要的 这个项目的主旨。 该项目的具体目标是：1)确定是否 CBP的乙酰转移酶活性是其修饰能力所必需的 果蝇的染色质结构。特异性CBP乙酰转移酶(AT) 在果蝇中与基因组dCBP同源的突变将 分析它们作为PEV修饰剂的作用。芯片分析将显示 CBP AT活性是否影响其参与染色质的能力 重塑复合体。2)确定与CBP相互作用的因素 染色质重塑。将对PEV的已知修饰剂进行分析 补偿CBP AT突变和相互作用的能力将得到确认 生化方面的。解决这些基本问题将有助于 为癌症和癌症等复杂疾病设计新的治疗方法 内分泌病。 在理查德博士的监督下，他获得了目前的K08奖项的支持 古德曼和萨拉·斯莫里克帮助路德兰博士发展为 作为一名科学家并在以下领域获得智力和技术基础 基因调控。来自R03奖项的支持将进一步提供必要的 为这项工作和培训提供技术支持和用品的资金 经验。OHSU和Vollum研究所继续提供丰富的知识分子 和物质设施资源，医学部继续 提供出色的部门支持。总体而言，这些资源提供 为路德兰博士完成交接提供了良好的环境 基因调控领域的科学独立性。

DESCRIPTION (provided by applicant): The pathophysiology of virtually any disease process can be described in terms of the misregulation of gene products. The conformation of DNA affects the cells? ability to access and utilize genes, and the process of altering chromatin structure (chromatin remodeling) is likely to be important in the control of gene expression. CREB-binding protein (CBP) is a critical regulator of expression for many genes, and our laboratory has demonstrated that the ability of CBP to modify other proteins through acetylation is critical for this function. We have also demonstrated that CPB is important in chromatin remodeling but it is still unclear how it does this and what factors it interacts with at the chromatin level. Addressing these issues is the main thrust of this project. The Specific Aims of this project are: 1) To determine whether the acetyltransferase activity of CBP is necessary for its ability to modify chromatin structure in Drosophila. Specific CBP acetyltransferase (AT) mutations which have been homogously targeted to genomic dCBP in the fly will be analyzed for their effect as modifiers of PEV. ChIP analysis will show whether CBP AT activity influences its ability to participate in chromatin remodeling complexes. 2) To identify factors that interact with CBP in the remodeling of chromatin. Known modifiers of PEV will be analyzed for their ability to compensate for CBP AT mutations and interactions will be confirmed biochemically. Addressing these fundamental questions will be helpful in designing novel treatments for complex diseases such as cancer and endocrinopathies. Support from his current K08 award under the supervision of Drs. Richard Goodman and Sarah Smolik has been instrumental in helping Dr. Ludlam develop as a scientist and gain an intellectual and technical foundation in the field of gene regulation. Support from a R03 award would further provide necessary funding for technical support and supplies for this work and training experience. OHSU and the Vollum Institute continue to provide rich intellectual and physical facility resources, and the Department of medicine continues to provide excellent departmental support. Collectively, these resources provide an excellent environment for the Dr. Ludlam to transition to complete scientific independence in the field of gene regulation.