Chemical Probes for Studying Formaldehyde Biology

用于研究甲醛生物学的化学探针

• 批准号: 10178026
• 负责人: Christopher J. Chang
• 金额: $ 31.37万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178026
• 关键词: Alcohol dehydrogenase; Aldehydes; Androgen Receptor; Biochemical; Biological; Biology; Calibration; Cancer Model; Carbon; Carcinogen exposure; Cell model; Cell physiology; Cells; Chemicals; Chemistry; Color; Complex; Coupled; Cysteine; Data; Detection; Development; Diabetes Mellitus; Disease; Environmental Carcinogens; Enzymes; Event; Flow Cytometry; Fluorescence; Formaldehyde; Generations; Genetic; Genetic Models; Goals; Health; Heart Diseases; Human; Image; Image Cytometry; Institution; Isotopes; Kinetics; Laboratories; Lead; Lysine; Maps; Metabolic; Metabolism; Methods; Modification; Molecular; Monitor; Neurodegenerative Disorders; Organism; Pathway interactions; Physiology; Play; Proteins; Proteolysis; Proteome; Proteomics; Reaction; Reagent; Receptor Signaling; Reporter; Role; Signal Transduction; Source; Structure; Techniques; Tetrahydrofolates; Time; Toxic Environmental Substances; Visualization; activity-based protein profiling; base; bile acid metabolism; biological systems; cell type; chemoproteomics; chronic liver disease; complex biological systems; demethylation; design; experimental study; fluorophore; follow-up; glyoxylate; imaging probe; improved; in vivo; innovation; knock-down; metabolomics; molecular imaging; new technology; protein profiling; public health relevance; ratiometric; scaffold; small molecule; stem; tool; urea cycle

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 exposure is also connected to a variety of other serious diseases ranging from neurodegenerative diseases, diabetes, and chronic liver and heart disorders. 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 are developing and applying 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 normal physiology and disease. This application will focus on creating new technologies that will enable highly selective molecular imaging of FA in cellular models to detect sources of FA generation, with accompanying chemoproteomics methods to identify targets of FA in genetic and cancer models where FA metabolism is compromised. Specific aims include developing new fluorescent FA probes with a variety of available colors and ratiometric detection, unbiased reactivity-based protein profiling (RBPP) methods to identify cysteine- and lysine-derived targets of FA in whole proteomes, and combining these complementary methods for studying sources and targets of FA biology.

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，被列为致癌物质， 暴露还与多种其他严重疾病有关，包括 神经退行性疾病、糖尿病以及慢性肝脏和心脏疾病。在 同时，身体在正常生理过程中产生这种活性羰基物质， 主要通过酶促去甲基化事件以及通过一碳 循环。我们正在开发和应用用于选择性成像和 生命系统中 FA 的蛋白质组学，以确定其分子来源和靶点， 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发生 有助于正常生理和疾病。该应用程序将专注于创建新的 能够在细胞模型中对 FA 进行高选择性分子成像的技术 检测 FA 产生的来源，并使用随附的化学蛋白质组学方法 确定 FA 代谢处于遗传和癌症模型中的 FA 靶标 妥协了。具体目标包括开发新的荧光 FA 探针 多种可用颜色和比率检测、基于反应性的公正蛋白质 分析 (RBPP) 方法可全面识别 FA 的半胱氨酸和赖氨酸衍生靶标 蛋白质组，并结合这些补充方法来研究来源和 FA 生物学的目标。