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

研究癌症和糖尿病能量稳态途径的化学和结构工具

• 批准号: 9381909
• 负责人: Michael Block Lazarus
• 金额: $ 40.26万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381909
• 关键词: Autophagocytosis; Biochemistry; Biology; Cell Nucleus; Cell physiology; Cells; Chemicals; Complex; Cytoplasm; Cytoplasmic Protein; Diabetes Mellitus; Disease; Enzymes; Eukaryotic Cell; Genetic Transcription; Goals; Homeostasis; Link; Malignant Neoplasms; Mammals; Metabolic; Modification; Nerve Degeneration; Nuclear Protein; Nuclear Proteins; O-GlcNAc transferase; Obesity; Organelles; Organism; Pathway interactions; Pharmaceutical Preparations; Play; Protein Glycosylation; Proteins; Quality Control; Role; Signal Transduction; System; Vision; cancer cell; chemotherapy; glycosylation; human disease; inhibitor/antagonist; novel; prevent; protein degradation; screening; structural biology; sugar; tool; tumor

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.

项目摘要 该实验室的总体目标是研究能量稳态途径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-GlcNAcylation和 自噬实验室的第一个主要重点是糖基化，它在生物体中起着基础作用 并且在几种人类疾病中被错误调节。哺乳动物中糖基化的一种独特形式涉及必需的 酶O-GlcNAc转移酶（OGT），其动态地将单个糖转移到细胞核和细胞质上 蛋白质来调节信号传导、转录和蛋白质降解。这种单一的酶负责 糖基化超过一千种底物。异常的OGT活性与人类疾病相关， 癌症、糖尿病、肥胖症和神经退化。然而，这种修改的生物学是相当复杂的 因为单一酶的底物丰富。这种复杂性阻碍了我们理解 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机能。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，研究基本酶。我们的主要 目的是阐明细胞核和细胞质蛋白糖基化在人类疾病中的复杂作用。 自噬是真核细胞利用的一种保守的途径，用于将物质从蛋白质回收到整体 用于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， 满足他们增加的能量需求并抵抗化疗。为了研究自噬，我们的主要目标是 开发一种新的化学抑制剂，抑制一种叫做ULK1的启动自噬的关键酶。我们的另一个目标是 通过发现协同靶向细胞的其他药物，发现与自噬作用的新型合成致命相互作用物 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， 寻找依靠阻断自噬的新的治疗组合。