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.

项目摘要/摘要 甲醛（FA）是一种无处不在的小分子，起着多种重要的重要性 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 物种，FA是一种主要的环境毒素，被归类为致癌物和 暴露还与各种其他严重疾病有关 神经退行性疾病，糖尿病和慢性肝脏和心脏病。在 同时，人体在正常生理过程中产生这种反应性羰基物种， 主要通过酶促的脱甲基化事件以及一碳 循环。我们正在开发和应用新的化学试剂进行选择性成像和 生命系统中FA的蛋白质组学，以识别其分子来源和靶标的 理解这种反应性小分子的长期目标是如何以及在什么情况下 有助于正常的生理和疾病。该应用程序将重点介绍创建新的 将在细胞模型中实现高度选择性分子成像的技术 检测FA生成的来源，并采用伴随的化学蛋白质组学方法 在FA代谢为遗传和癌症模型中识别FA的靶标 妥协。具体目的包括开发新的荧光FA探针 多种可用颜色和比例测定，公正反应性蛋白质 整体上识别FA的半胱氨酸和赖氨酸衍生靶标的分析（RBPP）方法 蛋白质组，并结合这些互补方法来研究来源和 FA生物学的靶标。