Molecular Imaging Agents for Monitoring Lysine Demethylases in Cell

用于监测细胞中赖氨酸脱甲基酶的分子成像剂

• 批准号: 10619655
• 负责人: Monika Raj
• 金额: $ 38.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619655
• 关键词: Biological; Cell Nucleus; Cells; Chemicals; Clinical; Combined Modality Therapy; Cytoplasm; Development; Disease; Elements; Enzymes; Family; Goals; Human; Hydrolysis; Inflammation; Lead; Lysine; Malignant Neoplasms; Metabolic Diseases; Methods; Methylation; Methyltransferase; Mitochondria; Molecular; Monitor; Organelles; Process; Proteins; Regulation; Reporting; Research; Resolution; Role; Signal Transduction; Techniques; Therapeutic; cancer therapy; cofactor; imaging agent; innovation; interest; methylome; molecular imaging; novel; programs; protein biomarkers; small molecule; therapeutic target; tool

PROJECT SUMMARY Protein lysine methylation is a reversible process controlled by lysine methyltransferases (KMTs or methyl writers) and lysine demethylases (KDMs or methyl erasers) in human cells. Most studies on these KMTs and KDMs have focused mainly on their functions inside the nucleus. More than half of these KMTs and KDMs, which are present in the nucleus are also localized in the cytoplasm but very little is known about their functions in this subcellular compartment. The abnormalities in these enzymes are directly associated with cancers, inflammation and other diseases. Despite the critical importance of the KDMs in different subcellular compartments, there is a substantial gap between their global analysis and effective methods available to achieve it. The long-term goal of this research program is to develop a mechanistic understanding of how “lysine methylome” is maintained at a subcellular level and how these chemical markers modulate cell signaling. The current focus is to develop a new class of chemical tools that report on KDM activities in living cells at a subcellular level. This new family of chemical tools will be deployed to determine the activity of KDMs in different subcellular compartments, and their regulation by substrates, and local cofactors. The primary biological interests right now deal with roles of KDMs outside of the nucleus, in particular, the cytoplasm and mitochondria, while pursuing mechanistic studies in the context of cancer. The proposed research contains four innovations to decode the intracellular KDM activities with subcellular resolution. First, is the development of new small molecule probes with unique chemoselectivity towards lysine, and high stability towards hydrolysis, which is ideal for studying KDMs in cells. Second, is the development of molecular imaging agents to monitor the activity of KDMs and how they are regulated inside the cells. Third, is to determine the activity of the specific KDMs by incorporating recognition elements on the probe. Fourth, is the development of organelle selective molecular imaging agents to study the role of KDMs in different subcellular compartments and their subcellular localization, which is currently impossible to determine with existing techniques. These probes are capable of determining KDM activities and their role in various diseased states thus of immense therapeutic interest. This research will have extensive applications in biomedical field by providing a better understanding of KDMs functions in different subcellular compartments, the molecular mechanisms of diseases, thus assist in the discovery of novel protein biomarkers, and combination-therapy for the treatment of cancer.

项目总结 蛋白质赖氨酸甲基化是由赖氨酸甲基转移酶控制的可逆过程 人类细胞中的赖氨酸脱甲基酶(KDM或甲基擦除器)。大多数关于这些KMT的研究和 KDM主要关注它们在核内的功能。这些KMT和KDM中有超过一半的人， 它们存在于细胞核中，也定位于细胞质中，但对它们的 在这个亚细胞隔间中发挥作用。这些酶的异常直接与 癌症、炎症和其他疾病。尽管KDM在不同的亚细胞中具有关键的重要性 在它们的全球分析和有效方法之间存在着很大差距 实现它。这项研究计划的长期目标是发展一种机械性的理解 “赖氨酸甲基组”维持在亚细胞水平，以及这些化学标志物如何调节细胞。 发信号。目前的重点是开发一类新的化学工具，报告KDM在生活中的活动 亚细胞水平上的细胞。这一新的化学工具系列将用于确定KDM的活性 在不同的亚细胞室中，以及底物和局部辅因子对它们的调节。初级阶段 目前生物学的兴趣涉及KDM在核外的作用，特别是细胞质和 线粒体，同时在癌症背景下进行机制研究。拟议的研究包括 四项创新，以亚细胞分辨率破译细胞内KDM活动。第一，是发展 新型小分子探针对赖氨酸具有独特的化学选择性，对赖氨酸具有高度的稳定性 水解，这是研究细胞中KDM的理想方法。第二，是分子显像剂的发展 以监测KDM的活性以及它们在细胞内是如何调节的。第三，是确定活动的 通过在探头上加入识别元素来识别特定的KDM。第四，细胞器的发育 选择性分子显像剂研究KDMS在不同亚细胞室中的作用及其意义 亚细胞定位，这是目前用现有技术无法确定的。这些探头是 能够确定KDM的活动及其在各种疾病状态中的作用，从而具有巨大的治疗作用 利息。本研究将为生物医学领域提供更好的认识和理解，具有广泛的应用前景 KDMS在不同亚细胞中的功能，疾病的分子机制，从而有助于 新的蛋白质生物标志物的发现，以及癌症治疗的联合疗法。