Parthanatos, PAAN/MIF nuclease Activation in Ischemic Injury

项目摘要/摘要： 中风和其他神经退行性疾病是导致死亡、残疾和质量丧失的主要原因 生活。谷氨酸神经毒性在脑缺血和神经退行性疾病中的重要性是很好的 有记录在案。在体外和体内给予谷氨酸及其类似物都能有效地通过 兴奋毒性机制。聚(ADP-核糖)聚合酶-1(PARP-1)在谷氨酸神经毒性和 脑梗塞。先前的研究表明，NO或过氧亚硝酸盐在谷氨酸中起着重要作用 兴奋性毒性和脑梗塞。在其他反应中，NO或过氧亚硝酸盐可以激活PARP-1， 它通过形成复杂的和支化的聚(ADP-核糖)(PAR)聚合物而导致细胞死亡。 细胞凋亡诱导因子(AIF)被认为是谷氨酸引发神经毒性的关键介质。 活性氧物种、DNA损伤和PAR聚合物。AIF存在于正常健康人的线粒体中 细胞，但在致命的刺激后以PARP-1依赖的方式移动到细胞核。阻止AIF来自 进入细胞核可以使细胞免于死亡。这种形式的细胞死亡最近被指定为 副死亡症，以区别于其他类型的细胞死亡，如凋亡，坏死性下垂或自噬 死亡。对安乐死级联反应的每一步的干预已被证明是对 各种型号。一旦AIF进入细胞核，就会发生大规模的DNA断裂(染色质分解 通过肝素相关的AIF(凋亡诱导因子)核酸酶(PAAN)，也称为MIF， 其中PAAN/MIF是急性缺血性疾病中细胞死亡的主要介质，其核酸酶 活动。最近，有研究认为炎性小体的激活需要MIF。因此，我们 建议探索一种一流的MIF核酸酶抑制剂在卒中模型中的应用，并探索 PAAN/MIF核酸酶活性在cGAS和STING通路及其后续激活中的作用 NLRP3激活。我们还将剖析PAAN/MIF核酸酶活性在神经元和小胶质细胞中的作用 在缺血损伤中。了解PAAN/MIF核酸酶活性在神经元损伤中的作用机制将有助于 到治疗神经退行性疾病和中风的创新治疗方法。

Project Summary/Abstract: Stroke and other neurodegenerative disorders are a leading cause of death, disability, and loss of quality of life. The importance of glutamate neurotoxicity in cerebral ischemia and neurodegenerative diseases is well documented. Both in vitro and in vivo administration of glutamate and its analogs effectively kill neurons via excitotoxic mechanisms. Poly(ADP-ribose) polymerase-1 (PARP-1) is pivotal in glutamate neurotoxicity and cerebral infarction. Prior studies indicate that NO, or peroxynitrite plays a prominent role in glutamate excitotoxicity and cerebral infarction. Amongst other responses NO, or peroxynitrite, can activate PARP-1, which leads to cell death through the formation of complex and branched poly(ADP-ribose) (PAR) polymer. Apoptosis inducing factor (AIF) has been identified as key mediator of neurotoxicity triggered by glutamate, reactive oxygen species, DNA damage and PAR polymer. AIF resides in the mitochondria in normal healthy cells but moves to the nucleus following a lethal stimulus in a PARP-1 dependent manner. Blocking AIF from entering the nucleus can spare cells from death. This form of cell death has recently been designated parthanatos to distinguish it from other types of cell death such as apoptosis, necroptosis or autophagic death. Interference with each step of the parthanatic cascade has been shown to be neuroprotective in a variety of models. Once AIF enters the nucleus, large scale DNA fragmentation (chromatinolysis) occurs through the Parthanatos Associated AIF (apoptosis-inducing factor) Nuclease (PAAN) also known as MIF, where PAAN/MIF is a major mediator of parthanatic cell death in acute ischemic disorders via its nuclease activity. Recently, MIF has been suggested to be required for inflammasome activation. Accordingly, we propose to explore the use of a first in class, MIF nuclease inhibitor in stroke models and explore the contributions of PAAN/MIF’s nuclease activity in the activation of cGas and STING pathway and subsequent NLRP3 activation. We will also dissect the role of PAAN/MIF’s nuclease activity in neurons versus microglia in ischemic injury. Understanding the mechanisms of PAAN/MIF’s nuclease activity in neuronal injury will lead to innovative therapeutic approaches to treat neurodegenerative diseases and stroke.