Chemical Probes to Study Formaldehyde Biology

研究甲醛生物学的化学探针

• 批准号: 10439184
• 负责人: Christopher J. Chang
• 金额: $ 48.33万
• 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/10439184
• 关键词: Acetaldehyde; Acute; Aldehydes; Anabolism; Back; Binding Sites; Biochemical; Biological; Biological Models; Biology; CRISPR/Cas technology; Carbon; Carcinogens; Cardiovascular Diseases; Catalysis; Cations; Cell model; Cells; Chemicals; Chemistry; Chronic; Color; Complement; Complex; Coupled; Cysteine; DNA Methylation; Data; Detection; Development; Diabetes Mellitus; Disease; Dyes; Environment; Environmental Carcinogens; Enzymes; Event; Fluorescent Probes; Formaldehyde; 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-Adenosylmethionine; Site; Site-Directed Mutagenesis; Source; Stress; Techniques; Technology; Time; Tissues; Toxic Environmental Substances; Transition Elements; Validation; Visualization; activity-based protein profiling; base; catalyst; chemoproteomics; chronic liver disease; 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.

项目概要/摘要 甲醛 (FA) 是一种普遍存在的小分子，具有多种重要作用 在人类健康和疾病中的作用。作为最简单的醛和反应性羰基 FA 是一种主要的环境毒素，被列为致癌物，并且 FA 暴露还与多种其他严重疾病有关，包括慢性病 肝脏疾病、癌症、心血管和神经退行性疾病以及糖尿病。 同时，身体在正常情况下会产生这种活性羰基物质。 生理学，主要通过酶促去甲基化事件以及通过单- 碳循环。我们寻求开发和应用用于选择性成像的新型化学试剂 和生命系统中 FA 的蛋白质组学，以确定其分子来源和目标， 了解这种反应性小分子如何以及在什么情况下发挥作用的长期目标 有助于生理和疾病。该应用程序将重点关注新的 能够在生物模型中对 FA 进行选择性分子成像以进行研究的技术 FA 生成和代谢的来源，以及相应的化学蛋白质组学方法 确定 FA 代谢受损的遗传模型中 FA 的靶标。具体的 目标包括开发用于 FA 和亚细胞成像的新型荧光探针 酶促氧化生成甲酸盐，应用无偏的基于活性的蛋白质分析 (ABPP) 鉴定整个蛋白质组中 FA 半胱氨酸衍生靶标的方法，并执行 生物化学和细胞研究破译 FA 靶标在调节一碳中的作用 代谢。