Grant: $342,350 - National Institutes of Health - Jun. 1, 2009
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Award Description: Specific Aim #1: Comprehensively analyze the underlying mechanisms and biochemical consequences of ATDC deacetylation by HDAC9 Immediately following the identification and cloning of HDAC9, many questions arose, such as: Does HDAC9 possess a unique function that is not shared with other HDACs? Does HDAC9 deacetylate a subset of proteins or specific lysine residues on a particular substrate that are distinct from those deacetylated by other HDACs? Using siRNA to specifically knockdown the expression of HDAC9, we found that HDAC9 may be responsible for the deacetylation of ATDC. In the first aim, we will systematically evaluate and obtain a comprehensive picture of the ATDC deacetylation sites acted on by HDAC9. We will also address whether the site-specific ATDC deacetylation mediated by HDAC9 is responsible for the biochemical consequences it induces. Specific Aim #2: Define the role of HDAC9 in the HDAC9-ATDC complex HDAC9 is localized to both the nucleus and cytoplasm of cells. While the role of HDAC9 in the deacetylation of histones in the nucleus is firmly established, the function of HDAC9 in non-histone deacetylation remains unclear. Because HDAC9 exists in a multi-subunit complex with the cytoplasmic protein ATDC, it is possible that additional non-histone proteins are substrates for HDAC9 besides ATDC. We propose to purify this novel HDAC9 protein complex, to systematically identify each of the complex subunits, and to determine if any of the protein subunits are HDAC9 substrates. Specific Aim #3: Clarify the biological consequences of ATDC deacetylation by HDAC9 Although the ATDC gene was discovered fifteen years ago based on its ability to complement the ionizing radiation (IR) sensitivity of fibroblasts, nothing is known regarding how the ATDC protein complements survival in irradiated cells. Our preliminary data indicating that ATDC binds to and regulates p53 activities, coupled with our findings that ATDC undergoes acetylation and is deacetylated by HDAC9, opens up the exciting possibility that the biological functions of ATDC are precisely controlled by HDAC9. In the third aim, we will determine whether deacetylation of ATDC by HDAC9 affects the ability of ATDC to complement radiosensitivity. Specifically, we will rigorously test the possibility that ATDC acetylation prevents the activation of p53 target genes and cellular apoptosis, and ultimately activates ATDC-mediated cell survival after IR.
Project Description: The purpose of this proposal is to study the interaction between two proteins – ataxia telangiectasia group D complementing (ATDC) and histone deacetylase 9 (HDAC9). AT is a human genetic disease characterized by immunological, neurological, and developmental defects, and an increased risk of cancer. ATDC has the ability to complement the ionizing radiation sensitivity of ataxia telangiectasia (AT) group D fibroblasts. Abnormal HDACs play a key role in many human diseases including cancer, neurodegenerative disorders, cardiac hypertrophy, and chronic obstructive pulmonary disease. A thorough understanding of HDACs and ATDC is a prerequisite to understanding their impact on human health and diseases. Public
Jobs Summary: Post Doc Fellow - The Postdoctoral Research Fellow is a post-graduate-level entry position in which the individual is responsible for assisting with research activities as well as conducting independent research projects when appropriate under limited supervision. Graduate Research Assistant - Performs research duties under the supervision of an appropriate faculty member. Such research duties may include, but are not limited to, assisting in lab research, community-based research activities, developing research and evaluation surveys, collecting data, analyzing data using software analyses programs, data presentation, and/or writing draft research reports.' Principal Investigator-Director of Research Project (Total jobs reported: 2)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 1, 2009. Help expand these official descriptions using the wiki below.