Parthanatos, PAAN/MIF nuclease Activation in Ischemic Injury

项目概要/摘要： 中风和其他神经退行性疾病是死亡、残疾和生活质量损失的主要原因。 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已被广泛研究 记录在案。谷氨酸及其类似物的体外和体内给药均能有效杀死神经元， 兴奋性毒性机制聚（ADP-核糖）聚合酶-1（PARP-1）在谷氨酸神经毒性和 脑梗死先前的研究表明，NO或过氧亚硝酸盐在谷氨酸中起着重要作用， 兴奋性毒性和脑梗死。在其他反应中，NO或过氧亚硝酸盐可以激活PARP-1， 其通过形成复杂和支化的聚（ADP-核糖）（PAR）聚合物导致细胞死亡。 细胞凋亡诱导因子（AIF）已被确定为谷氨酸引发的神经毒性的关键介质， 活性氧、DNA损伤和PAR聚合物。AIF存在于正常健康人的线粒体中， 细胞，但在致死刺激后以PARP-1依赖性方式移动到细胞核。阻止AIF从 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 parthanatos，以区别于其他类型的细胞死亡，如凋亡，坏死性凋亡或自噬 死亡干扰parthanatic级联反应的每一步已经被证明是神经保护性的， 各种型号。一旦AIF进入细胞核，就会发生大规模的DNA片段化（染色质溶解 通过Parthanatos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通过其核酸酶引起的旁致死性细胞死亡的主要介质 活动最近，MIF被认为是炎性小体激活所必需的。因此我们 建议探索使用一流的MIF核酸酶抑制剂在中风模型中的应用，并探索 PAAN/MIF的核酸酶活性在cGas和STING途径的活化中的贡献以及随后的 NLRP 3激活。我们还将分析PAAN/MIF的核酸酶活性在神经元和小胶质细胞中的作用 在缺血性损伤中。了解PAAN/MIF的核酸酶活性在神经元损伤中的作用机制，将有助于我们更好地了解PAAN/MIF在神经元损伤中的作用。 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.