Chemical Probes for Studying Formaldehyde Biology

项目摘要/摘要 甲醛(FA)是一种普遍存在的小分子，它发挥着多种重要的 在人类健康和疾病中的作用。作为最简单的醛和活性羰基 种，FA是一种主要的环境毒素，被归类为致癌物质和 接触也与其他各种严重的疾病有关，包括 神经退行性疾病、糖尿病、慢性肝病和心脏病。在 同时，身体在正常生理状态下会产生这种活性碳基物质， 主要是通过酶去甲基化事件以及通过一碳 周而复始。我们正在开发和应用新的化学试剂，用于选择性成像和 生命系统中FA的蛋白质组学研究以确定其分子来源和靶点 长期的目标是了解这种反应性小分子是如何以及在什么背景下 有助于正常的生理和疾病。此应用程序将专注于创建新的 在细胞模型中实现FA的高选择性分子成像的技术 为了检测FA的产生来源，并伴随着化学蛋白质组学方法 在代谢FA的遗传和癌症模型中确定FA的靶点 妥协了。具体目标包括开发新的荧光FA探针， 多种可用的颜色和比率检测，基于反应性的无偏蛋白质 甲酸半胱氨酸和赖氨酸衍生靶标的整体鉴定方法 蛋白质组，并结合这些互补的方法来研究来源和 FA生物学的靶标。

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.