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: 10226372
• 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/10226372
• 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.

项目概要 蛋白质赖氨酸甲基化是一个由赖氨酸甲基转移酶（KMT 或甲基转移酶）控制的可逆过程。 作家）和人类细胞中的赖氨酸去甲基酶（KDM 或甲基擦除器）。大多数关于这些国民党的研究 KDM 主要关注其在细胞核内的功能。这些国民党和 KDM 中有一半以上， 存在于细胞核中的物质也存在于细胞质中，但人们对它们知之甚少。 在此亚细胞区室中发挥作用。这些酶的异常与 癌症、炎症和其他疾病。尽管 KDM 在不同的亚细胞中至关重要 区室，他们的全球分析和有效方法之间存在很大差距 实现它。该研究计划的长期目标是深入了解如何 “赖氨酸甲基化组”维持在亚细胞水平以及这些化学标记如何调节细胞 发信号。目前的重点是开发一类新型化学工具，报告生活中的 KDM 活动 亚细胞水平的细胞。这一新的化学工具系列将用于确定 KDM 的活性 在不同的亚细胞区室中，及其底物和局部辅助因子的调节。初级 目前的生物学兴趣涉及细胞核外 KDM 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。拟议的研究包含 通过亚细胞分辨率解码细胞内 KDM 活动的四项创新。首先，是发展 新型小分子探针对赖氨酸具有独特的化学选择性，并且对赖氨酸具有高稳定性 水解，这是研究细胞中 KDM 的理想选择。二、是分子显像剂的发展 监测 KDM 的活性以及它们在细胞内的调节方式。三是确定活性 通过在探针上结合识别元件来识别特定的 KDM。四、是细胞器的发育 选择性分子显像剂研究 KDM 在不同亚细胞区室中的作用及其作用 亚细胞定位，目前现有技术无法确定。这些探针是 能够确定 KDM 活性及其在各种疾病状态中的作用，因此具有巨大的治疗作用 兴趣。这项研究将通过提供更好的理解，在生物医学领域具有广泛的应用。 KDMs 在不同亚细胞区室中发挥作用，了解疾病的分子机制，从而有助于 新型蛋白质生物标志物的发现以及治疗癌症的联合疗法。