Neuroprotection by inhibition of the postsynaptic density protein 95 (PSD95)

通过抑制突触后密度蛋白 95 (PSD95) 实现神经保护

• 批准号: 491524722
• 负责人: Dr. Elena Kurz
• 金额: --
• 依托单位: Krembil Research Institute
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/491524722?language=en
• 关键词: Neuroprotection; inhibition; postsynaptic; density; protein

Since the beginning of my residency in the neurosurgical department of the Universitätsmedizin Mainz I have been an investigator in the neurovascular research team of Dr. Keric. The planned research fellowship at Krembil Research Institute offers me the opportunity to gain new experiences and to deepen experimental methods which will be an important step towards habilitation in the neurovascular field. The research team of Dr. Tymianski is specialized in the field of neuroprotection and has published multiple high-impact studies about neurotoxic mechanisms and inhibition of signaling pathways leading to cell death. The experimental investigations are proof for a high quality of research and an excellent infrastructure of the laboratory. Tymianski et al. have developed an inhibitor of the postsynaptic density protein 95 named Nerinetide, which interrupts the activation of Nitric oxide (NO)-Synthase by overstimulated NMDA receptors. Thus, Nerinetide prevents the production of an excitotoxic concentration of NO and the resulting neurotoxicity. The group has already shown promising results in in vivo studies in rats and makaques. The subsequent randomized, controlled, multicentric, double blinded study named ESCAPE-NA1 proved a better functional outcome and smaller volumes of ischemia in stroke patients treated with Nerinetide. Though, a reduction of effect has been detected when the PSD95 inhibitor has been simultaneously provided with lytic drugs like Alteplase. The activation of plasmin by rtPA causes lysis of the thrombus but it causes a fast degradation of the PSD95 inhibitor concurrently. Nevertheless, thrombolysis is an essential step in the therapy of stroke patients. That’s why it is important to develop a plasmin resistant variant of Nerinetide. As a result the neuroprotective effect of a plasmin resistant PSD95 inhibitor combined with the benefit of thrombolysis could lead to an improvement of clinical outcome for affected patients. During my fellowship I will take part in the investigations testing the new plasmin resistant PSD95 inhibitor in vivo. Dosing, interactions, compatibility, and pharmacokinetics will be analyzed. The neuroprotective capacity will be evaluated in the transient middle cerebral artery occlusion model in rats. Based on the results further studies will be conducted leading to the introduction of the plasmin resistant PSD95 inhibitor in clinical routine.Furthermore, it has been shown by Tymianski et al. that the inhibition of PSD95 is beneficial in inflammatory and degenerative neurological diseases, as well. Other studies have indicated a neuroprotective effect of PSD95 inhibition in patients with intracerebral hemorrhage (ICH) by interruption of excitotoxic effects and reduction of secondary brain injury.After my return I plan to benefit from my newly developed skills for further investigations of neurotoxic effects and to transfer my gained knowledge on the ICH model which is established in our laboratory.

自从我开始在美因茨大学神经外科住院医生以来，我一直是Keric博士神经血管研究团队的研究员。在Krembil研究所计划的研究奖学金为我提供了获得新经验和深化实验方法的机会，这将是在神经血管领域迈向hepatitis的重要一步。Tymianski博士的研究团队专注于神经保护领域，并发表了多项关于神经毒性机制和抑制导致细胞死亡的信号通路的高影响力研究。实验研究证明了高质量的研究和实验室的良好基础设施。Tymianski等人已经开发了一种名为Nerinetide的突触后密度蛋白95的抑制剂，其通过过度刺激的NMDA受体中断一氧化氮（NO）合酶的激活。因此，Nerinetide可防止产生兴奋性毒性浓度的NO和由此产生的神经毒性。该小组已经在大鼠和猕猴的体内研究中显示出有希望的结果。随后的随机、对照、多中心、双盲研究ESCAPE-NA 1证明了接受Nerinetide治疗的卒中患者的功能结局更好，缺血体积更小。然而，当PSD 95抑制剂与裂解药物如阿替普酶同时提供时，已经检测到效果降低。rtPA激活纤溶酶导致血栓溶解，但同时导致PSD 95抑制剂快速降解。然而，溶栓是中风患者治疗中必不可少的步骤。这就是为什么开发耐纤溶酶的Nerinetide变体很重要。因此，纤溶酶抗性PSD 95抑制剂的神经保护作用与溶栓的益处相结合可导致受影响患者的临床结果的改善。在我的研究期间，我将参加在体内测试新的抗纤溶酶PSD 95抑制剂的研究。将分析给药、相互作用、相容性和药代动力学。将在大鼠短暂性大脑中动脉闭塞模型中评价神经保护能力。基于这些结果，将进行进一步的研究，从而在临床常规中引入抗纤溶酶的PSD 95抑制剂。此外，Tymianski等人已经表明，PSD 95的抑制对炎症和退行性神经系统疾病也是有益的。其他研究表明，PSD 95抑制剂对脑出血（ICH）患者具有神经保护作用，可阻断兴奋性毒性作用，减少继发性脑损伤。回国后，我计划从我新发展的技能中受益，进一步研究神经毒性作用，并将我在本实验室建立的ICH模型上获得的知识传授给他人。