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.
