A High Throughput Screen for Inhibitors of a Novel Necrotic Cell Death Pathway

新型坏死细胞死亡途径抑制剂的高通量筛选

• 批准号: 7304402
• 负责人: JUNYING YUAN
• 金额: $ 2.5万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304402
• 关键词: 1-Methyl-4-phenylpyridinium; Affinity; Apoptosis; Apoptotic; Biological Assay; Biotin; Caspase; Cell Death; Cell physiology; Cells; Cellular biology; Chemicals; Chemistry; Class; Collection; Drug Kinetics; Fibroblasts; Funding; Goals; Human; Inhibition of Apoptosis; Institutes; Investigation; Jurkat Cells; Lead; Lethal Dose 50; Modeling; Molecular; Molecular Bank; Morphology; Mus; Necrosis; Pathway interactions; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Radioactive; Reagent; Screening procedure; Series; Solubility; Stroke; System; TNF gene; Testing; Time; Toxic effect; United States Food and Drug Administration; United States National Institutes of Health; base; cell suicide; cell type; chemical resource; high throughput screening; improved; in vivo; inhibitor/antagonist; mouse model; novel; small molecule

DESCRIPTION (provided by applicant): The objective of this proposal is to isolate additional necrostatins for understanding the molecular mechanism of necroptosis. Apoptotic pathways have been studied extensively during the past decade. However, it has become increasingly clear that apoptosis is not the only cellular suicide mechanism. For example, in a subset of cell types, inhibition of caspases when cells are stimulated by FasL or TNFa lead to inhibition of apoptosis but cells die with necrotic morphology through a cellular process termed necroptosis. Necroptosis has been shown to be a promising target for the treatment of stroke with an extended time window. Necrostatins are small molecules that specifically inhibits necroptosis but not apoptosis. This application is to carry out a mechanistic study of necroptosis by utilizing unique chemical resources at NIH to generate small molecule affinity reagents for target identification, and to identify new necrostatins in order to meet the highly challenging goal of developing an anti-stroke drug. This project is to identify small molecule inhibitors of a novel cell death pathway, termed necroptosis. Necroptosis has been shown to be a promising target for the treatment of stroke as it represents a type of delayed cell death in stroke and offers an extended time window for therapy.

描述(申请人提供)：这项建议的目标是分离更多的坏死他汀类药物，以了解坏死性下垂的分子机制。在过去的十年中，人们对细胞凋亡途径进行了广泛的研究。然而，越来越清楚的是，细胞凋亡并不是唯一的细胞自杀机制。例如，在一组细胞类型中，当细胞受到FasL或TNFa刺激时，抑制caspase会导致细胞凋亡的抑制，但细胞会通过一种称为坏死性下垂的细胞过程以坏死形态死亡。坏死性下垂已被证明是治疗中风的一个有希望的靶点，具有延长的时间窗口。Necrostatins是专门抑制坏死性下垂的小分子，但不能抑制细胞凋亡。这项应用是通过利用NIH独特的化学资源来进行坏死性下垂的机制研究，以产生用于靶标识别的小分子亲和试剂，并鉴定新的坏死素，以满足开发抗中风药物的高挑战性目标。这个项目是为了识别一种新的细胞死亡途径的小分子抑制剂，称为坏死性下垂。坏死性下垂已被证明是治疗中风的一个有前途的靶点，因为它代表了中风中一种延迟性的细胞死亡，并为治疗提供了更长的时间窗口。