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: 10226148
• 负责人: Michael Block Lazarus
• 金额: $ 42.35万
• 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/10226148
• 关键词: Autophagocytosis; Biochemistry; Biology; Cell Nucleus; Cell physiology; Cells; Chemical Structure; 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; Structure; 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