Human Histone Deacetylase Proteins

描述(由申请人提供)：该项目的长期目标是区分11种已知的人类组蛋白脱乙酰基酶(HDAC)蛋白的单独功能。HDAC蛋白是通过去乙酰化核小体组蛋白来抑制转录的转录因子。使用HDAC蛋白的小分子抑制剂的研究已经证明了它们在细胞周期调节、组织分化和癌症形成中的重要性。事实上，正在开发HDAC蛋白的小分子抑制剂来治疗某些疾病，包括髓系白血病。然而，小分子抑制剂对所有11种已知的人类HDAC蛋白的非特异性抑制使确定哪些HDAC在疾病发展中起到了致病作用变得复杂起来。对已知的每一种HDAC蛋白的生物学相关性进行严格的表征将有助于开发治疗疾病的药物。 这项提案的短期目标是着重说明人类发展和可持续发展1的个别职能。将采用生物有机方法，其中将使用小分子HDAC抑制剂曲古抑素来推断HDAC1的单独功能。具体地说，改变了对小分子抑制敏感性的HDAC1突变蛋白将被用来证明它们对基因表达的单独影响。这项建议中的实验旨在表征HDAC1的特定活性，作为确定所有人类HDAC蛋白的单独功能的第一步。该项目将为最终开发以HDAC蛋白为靶点的药物制剂奠定基础。

DESCRIPTION (provided by applicant): The long-term goal of this project is to distinguish between the individual functions of the eleven known human histone deacetylase (HDAC) proteins. HDAC proteins are transcription factors that repress transcription by deacetylating nucleosomal histones. Studies using small molecule inhibitors of HDAC proteins have demonstrated their importance in cell cycle regulation, tissue differentiation, and cancer formation. In fact, small molecule inhibitors of HDAC proteins are being developed to treat certain diseases, including myeloid leukemia. The nonspecific inhibition of all eleven known human HDAC proteins by small molecule inhibitors, however, complicates the determination of which HDAC plays a causative role in disease development. Rigorous characterization of the biological relevance of each of the known HDAC proteins would aid in development of pharmaceutical agents to treat disease. The short-term goal of this proposal is to focus on characterizing the individual functions of HDAC1. A bioorganic approach will be taken where the small molecule HDAC inhibitor trichostatin will be used to deduce the individual functions of HDAC1. Specifically, mutant protein of HDAC1 that has altered sensitivity to small molecule inhibition will be used to document their individual effects on gene expression. The experiments in this proposal aim to characterize the specific activities of HDAC1 as a first step toward identifying the individual functions of all human HDAC proteins. The proposed project will lay the foundation for the ultimate development of pharmaceutical agents targeting HDAC proteins.