Mechanism and Inhibition of Histone Modifications

组蛋白修饰的机制和抑制

基本信息

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
项目类别：
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

项目摘要

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甲基化代表一种多功能后翻译后修饰发生在所有真核生物中。蛋白甲基转移酶调节大量细胞过程从基因转录，RNA剪接，翻译，代谢途径到信号转导不等。许多发现蛋白甲基转移酶在常见的人类疾病中过表达或突变，例如癌症，炎症，糖尿病，神经系统疾病和感染。因此，蛋白甲基转移酶是在药物发现中，高度有希望的新型分子靶标。但是，大多数的生物学功能蛋白甲基转移酶在决定正常生理和疾病途径方面仅定义很差。我们的长期研究目标是阐明生物学途径，其中关键的蛋白甲基转移酶有助于诸如癌症和感染等顽固疾病的发病机理，同时发现用于蛋白甲基转移酶靶向疗法的新结构化学型。当前的研究计划是旨在研究通过钥匙催化的蛋白甲基化的分子机制和功能甲基转移酶。我们的努力与创新化学的开发和应用相结合并有助于生物学方法和工具。基于我们最近的初步结果，我们将实施实验以阐明新型分子机制和蛋白精氨酸甲基转移酶（PRMT）活性的调节。我们将扩展我们研究未开发的蛋白甲基转移酶的活动，结构和功能的努力，包括那些在不同生物中的人，例如感染性病原体。将指示开发的特殊努力同工型选择性调节剂和重要PRMT成员的探针，并将其应用于PRMT- 调节细胞途径和疾病过程。将投入进一步的努力来询问潜在的跨界蛋白甲基化与赖氨酸乙酰化在策划生物学调节中的相互作用。结果拟议的研究将对调节机制和生物学有深入的了解蛋白甲基化在控制正常生理和疾病病理学中的重要性，并翻译实验室研究导致治疗蛋白甲基转移酶控制的治疗候选者疾病。