Chemical Probes to Study Formaldehyde Biology

研究甲醛生物学的化学探针

• 批准号: 10599351
• 负责人: Christopher J. Chang
• 金额: $ 47.7万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599351
• 关键词: Acetaldehyde; Acute; Aldehydes; Anabolism; Binding Sites; Biochemical; Biological; Biological Models; Biology; CRISPR/Cas technology; Carbon; Carcinogens; Cardiovascular Diseases; Catalysis; Cations; Cell model; Cells; Chemicals; Chemistry; Chronic; Classification; Color; Complement; Complex; Coupled; Cysteine; DNA Methylation; Data; Detection; Development; Diabetes Mellitus; Disease; Dyes; Environment; Environmental Carcinogens; Enzymes; Event; Fluorescent Probes; Formaldehyde; Formates; Generations; Genetic Models; Goals; Health; HepG2; Hepatocyte; Human; Hydrogenation; Image; In Vitro; Isotopes; Knock-out; Knockout Mice; Liver diseases; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolism; Methods; Methylation; Mitochondria; Modeling; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Organism; Peptides; Permeability; Physiology; Play; Proteins; Proteolysis; Proteome; Proteomics; RNA; RNA methylation; Reaction; Reagent; Research; Research Personnel; Resolution; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Site; Site-Directed Mutagenesis; Source; Stress; Techniques; Technology; Time; Tissues; Toxic Environmental Substances; Transition Elements; Validation; Visualization; activity-based protein profiling; catalyst; chemoproteomics; chronic liver disease; coping; demethylation; fluorophore; imaging probe; innovation; lipophilicity; methionine adenosyltransferase; molecular imaging; mouse model; new technology; novel; oxidation; public health relevance; ratiometric; scaffold; small molecule; stem; subcellular targeting

Project Summary/Abstract Formaldehyde (FA) is a ubiquitous small molecule that plays a diverse array of important roles in human health and disease. As the simplest aldehyde and reactive carbonyl species, FA is a major environmental toxin that is classified as a carcinogen, and FA exposure is also connected to a variety of other serious diseases ranging from chronic liver disorders to cancer, cardiovascular and neurodegenerative diseases, and diabetes. At the same time, the body produces this reactive carbonyl species during normal physiology, primarily through enzymatic demethylation events as well as through the one- carbon cycle. We seek to develop and apply new chemical reagents for selective imaging and proteomics of FA in living systems to identify its molecular sources and targets, with the long-term goal of understanding how and in what context this reactive small molecule contributes to both physiology and disease. This application will focus on new technologies to enable selective molecular imaging of FA in biological models to study sources of FA generation and metabolism, with accompanying chemoproteomics methods to identify targets of FA in genetic models where FA metabolism is compromised. Specific aims include developing new fluorescent probes for subcellular imaging of FA and enzymatic oxidation to formate, applying unbiased activity-based protein profiling (ABPP) methods to identify cysteine-derived targets of FA in whole proteomes, and performing biochemical and cellular studies to decipher roles of FA targets in regulating one-carbon metabolism.

项目总结/摘要 甲醛（FA）是一种普遍存在的小分子，在人体内起着多种重要的作用。 在人类健康和疾病中的作用。作为最简单的醛和活性羰基 FA是一种主要的环境毒素，被列为致癌物质， 暴露也与各种其他严重疾病有关， 肝病、癌症、心血管和神经退行性疾病以及糖尿病。 与此同时，身体在正常代谢过程中产生这种活性羰基物质。 生理学，主要是通过酶促去甲基化事件以及通过一个- 碳循环我们寻求开发和应用新的化学试剂用于选择性成像 和蛋白质组学的FA在生活系统中，以确定其分子来源和目标， 长期目标是了解这种反应性小分子如何以及在什么情况下 对生理和疾病都有影响该应用程序将专注于新的 技术，使生物模型中的FA的选择性分子成像研究 FA产生和代谢的来源，以及伴随的化学蛋白质组学方法 在FA代谢受损的遗传模型中确定FA的靶点。具体 目标包括开发用于FA亚细胞成像的新荧光探针， 酶促氧化为甲酸盐，应用无偏的基于活性的蛋白质谱分析（ABPP） 在整个蛋白质组中鉴定FA的半胱氨酸衍生靶标的方法， 生物化学和细胞研究，以破译FA靶点在调节一碳中的作用 新陈代谢.