Chemical and structural tools to study energy homeostasis pathways in cancer and diabetes

项目摘要 该实验室的总体目标是研究能量稳态通路在人类疾病中的作用。 结构和化学工具。我们的实验室专注于两个主要的基本途径：O-GlcN酰化和 自噬。该实验室的第一个主要关注点是糖基化，它在活着的生物体中发挥着基础作用。 并在几种人类疾病中受到错误的调控。哺乳动物体内的一种独特形式的糖基化涉及到必需的 O-GlcNAc转移酶(OGT)，动态地将单糖转移到细胞核和细胞质上 调节信号、转录和蛋白质降解的蛋白质。这种单一的酶负责 在一千种底物上糖基化。OGT活性异常与人类疾病有关，如 癌症、糖尿病、肥胖症和神经变性。然而，这种修饰的生物学原理相当复杂。 因为单一酶的底物很丰富。这种复杂性阻碍了人们对 哪些底物对人类疾病很重要，OGT如何识别它们，以及代谢如何变化 通过这种酶改变细胞的生理。我们试图更好地理解这一机制 通过生物化学、结构生物学和化学生物学的结合而产生的基础酶。我们的专业 目的是阐明核蛋白和细胞质蛋白糖基化在人类疾病中的复杂作用。 自噬是真核细胞将物质从蛋白质循环到整体的一条保守的途径。 能量和质量控制的细胞器。最近的研究表明，癌细胞依赖于自噬来 满足他们日益增长的能量需求，并抵抗化疗。为了研究自噬，我们的主要目标是 开发一种名为ULK1的启动自噬的关键酶的新化学抑制剂。我们的另一个目标是 通过发现其他协同靶向细胞的药物，发现具有自噬功能的新型合成致死相互作用因子 当自噬被抑制时。我们的愿景是开发先进的筛查系统，以更好地模拟肿瘤和 寻找依赖于阻断自噬的新的治疗组合。

Project Abstract The overall goal of the lab is to study the role of energy homeostasis pathways in human disease using structural and chemical tools. Our lab focuses on two major fundamental pathways: O-GlcNAcylation and autophagy. The first major focus on the lab is on glycosylation, which plays a fundamental role in living organisms and is misregulated in several human diseases. A unique form of glycosylation in mammals involves the essential enzyme O-GlcNAc transferase (OGT), which dynamically transfers a single sugar on to nuclear and cytoplasmic proteins to modulate signaling, transcription, and protein degradation. This single enzyme is responsible for glycosylating over a thousand substrates. Aberrant OGT activity is associated with human diseases such as cancer, diabetes, obesity, and neurodegeneration. However, the biology of this modification is quite complex because of the abundance of substrates for a single enzyme. This complexity has prevented an understanding of which substrates are important for human diseases, how OGT recognizes them, and how metabolic changes alter the physiology of cells through this enzyme. We seek to better understand the mechanism of this fundamental enzyme through a combination of biochemistry, structural biology, and chemical biology. Our major goal is to clarify the complex role that nuclear and cytoplasmic protein glycosylation has in human disease. Autophagy is a conserved pathway that eukaryotic cells use to recycle materials from proteins to whole organelles for energy and quality control. It has recently been shown that cancer cells rely on autophagy to satisfy their increased energy demands and to resist chemotherapy. To study autophagy, our major goals are developing new chemical inhibitors of a key enzyme that initiates autophagy called ULK1. Our other goal is to find novel synthetic lethal interactors with autophagy by discovering other drugs that synergistically target cells when autophagy is inhibited. Our vision is to develop advance screening systems to better mimic tumors and look for new combinations of treatment that rely on blocking autophagy.