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

描述（由申请方提供）：本提案的目的是分离其他坏死抑制素，以了解坏死性凋亡的分子机制。在过去的十年中，细胞凋亡途径已经被广泛研究。然而，越来越清楚的是，凋亡不是唯一的细胞自杀机制。例如，在细胞类型的子集中，当细胞被FasL或TNF α刺激时，半胱天冬酶的抑制导致细胞凋亡的抑制，但细胞通过称为坏死性凋亡的细胞过程以坏死形态死亡。坏死性下垂已被证明是一个有前途的目标，治疗中风的时间窗延长。坏死抑制素是特异性抑制坏死性凋亡但不抑制凋亡的小分子。本申请旨在通过利用NIH独特的化学资源进行坏死性凋亡的机制研究，以产生用于靶点鉴定的小分子亲和试剂，并鉴定新的坏死抑制素，以满足开发抗卒中药物的高度挑战性目标。这个项目是确定一种新的细胞死亡途径，称为坏死性凋亡的小分子抑制剂。坏死性凋亡已被证明是治疗中风的一个有前途的目标，因为它代表了中风中的一种延迟细胞死亡，并提供了延长的治疗时间窗。

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.