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 基因产物的错误调节。DNA的构象会影响 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）可能是重要的， 控制基因表达。CREB结合蛋白（CBP）是一种重要的调节因子， 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于 这个函数我们还证明了CPB在染色质中的重要性 重塑，但目前还不清楚它是如何做到这一点，以及什么因素， 在染色质水平上相互作用。解决这些问题是主要的 这个项目的推力。 本项目的具体目标是：1）确定是否 CBP的乙酰转移酶活性是其修饰 果蝇的染色质结构特异性CBP乙酰转移酶（AT） 在果蝇中同源靶向基因组dCBP的突变将 分析其作为PEV改性剂的效果。ChIP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)为了确定与CBP相互作用的因素 染色质重塑。将分析已知的PEV改性剂的 将确认补偿CBP AT突变和相互作用的能力 生物化学解决这些基本问题将有助于 为癌症等复杂疾病设计新的治疗方法， 内分泌疾病 在Richard博士的监督下，他目前获得的K08奖提供了支持。 古德曼和莎拉·斯莫利克在帮助卢德拉姆博士发展为 一个科学家，并获得在该领域的知识和技术基础 基因调控R03奖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 体验. OHSU和Vollum研究所继续提供丰富的知识 和物理设施资源，医学部继续 提供出色的部门支持。这些资源共同提供 一个很好的环境让Ludlam博士完成 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.