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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质甲基化代表了一种多用途的翻译后修饰