Mechanism and Inhibition of Histone Modifications

组蛋白修饰的机制和抑制

• 批准号: 10621492
• 负责人: Y. George Zheng
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621492
• 关键词: Acetylation; Arginine; Biological; Biological Process; Biology; Cell physiology; Chemicals; Coupled; Development; Diabetes Mellitus; Disease; Disease Pathway; Enzymes; Epigenetic Process; Genetic Transcription; Goals; Infection; Inflammation; Investments; Laboratory Research; Lysine; Malignant Neoplasms; Mediating; Metabolic Pathway; Metabolism; Methods; Methylation; Methyltransferase; Molecular; Molecular Target; Mutate; Organism; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Physiology; Post-Translational Protein Processing; Process; Protein Isoforms; Protein Methylation; Protein Methyltransferases; Protein-Arginine N-Methyltransferase; RNA Splicing; Regulation; Research; Signal Transduction; Structure; Translating; Translations; design; drug discovery; experimental study; histone modification; human disease; innovation; member; nervous system disorder; novel; novel therapeutics; overexpression; pathogen; programs; protein function; targeted treatment; therapeutic candidate; therapy development; tool

Protein methylation on arginine and lysine residues represents a type of versatile posttranslational modifications occurring in all eukaryotic organisms. Protein methyltransferases regulate a plethora of cellular processes ranged from gene transcription, RNA splicing, translation, metabolic pathways, to signal transduction. Many protein methyltransferases are found to be overexpressed or mutated in common human diseases such as cancer, inflammation, diabetes, neurological disorders, and infection. Hence, protein methyltransferases are highly promising novel molecular targets in drug discovery. However, biological functions of the majority of protein methyltransferase enzymes in dictating normal physiology and disease pathways are only poorly defined. Our long-term research goal is to elucidate biological pathways whereby key protein methyltransferases contribute to the pathogenesis of recalcitrant diseases such as cancer and infection, and meanwhile to discover new structural chemotypes for protein methyltransferase-targeted therapy. The present research program is aimed at investigating molecular mechanisms and functions of protein methylation catalyzed by key methyltransferases. Our effort is coupled with and aided by development and application of innovative chemical biology methods and tools. Built upon our recent preliminary results, we will implement experiments to elucidate novel molecular mechanisms and regulation of protein arginine methyltransferase (PRMT) activities. We will extend our efforts to investigate the activity, structure and function of untapped protein methyltransferases, including those in different organisms such as infectious pathogens. Particular efforts will be directed to develop isoform-selective modulators and probes for important PRMT members and apply them to elucidate PRMT- regulated cellular pathways and disease processes. Further efforts will be invested to interrogate potential cross- interactions of protein methylation with lysine acetylation in orchestrating biological regulation. The results of the proposed research together will yield an in-depth understanding of the regulatory mechanism and biological significance of protein methylation in the control of normal physiology and disease pathology, and translate laboratory research leads into therapeutic candidates for the treatment of protein methyltransferase-controlled ailments.

精氨酸和赖氨酸残基上的蛋白质甲基化是一种多功能的翻译后修饰 存在于所有真核生物中的。蛋白质甲基转移酶调节过多的细胞过程 从基因转录、RNA剪接、翻译、代谢途径到信号转导。许多 蛋白质甲基转移酶在常见的人类疾病中被发现过度表达或突变，例如 癌症、炎症、糖尿病、神经疾病和感染。因此，蛋白质甲基转移酶是 在药物发现中极具前景的新分子靶点。然而，大多数细胞的生物学功能 蛋白质甲基转移酶在决定正常生理和疾病途径中的作用还不是很清楚。 我们的长期研究目标是阐明关键蛋白甲基转移酶 有助于癌症和感染等顽固性疾病的发病机制，同时发现 蛋白质甲基转移酶靶向治疗的新结构化学类型。目前的研究计划是 旨在研究KEY催化蛋白质甲基化的分子机制和功能 甲基转移酶。我们的努力是与创新化学品的开发和应用相结合并得到帮助的 生物学方法和工具。在我们最近的初步结果的基础上，我们将进行实验来阐明 蛋白质精氨酸甲基转移酶(PRMT)活性的新分子机制和调控。我们会 继续努力研究未开发的蛋白质甲基转移酶的活性、结构和功能， 包括不同生物体中的那些，如传染性病原体。将作出特别努力，以发展 重要PRMT成员的异构体选择性调节剂和探针，并应用于阐明PRMT- 受调控的细胞通路和疾病过程。将投入进一步的努力来审问潜在的交叉 蛋白质甲基化与赖氨酸乙酰化在协调生物调节中的相互作用。评选结果 拟议的研究将产生对调节机制和生物学的深入理解。 蛋白质甲基化在控制正常生理和疾病病理中的意义及其翻译 实验室研究引导出治疗蛋白质甲基转移酶控制的候选药物 病痛。