Targeting PSD Proteins in the Treatment of CNS Injury

靶向 PSD 蛋白治疗中枢神经系统损伤

• 批准号: 7115944
• 负责人: MICHAEL TYMIANSKI
• 金额: $ 24.03万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115944
• 关键词: NMDA receptors; brain injury; central nervous system; chemotherapy; cytoskeletal proteins; drug design /synthesis /production; drug screening /evaluation; inhibitor /antagonist; injury; laboratory mouse; laboratory rat; nerve /myelin protein; neurons; neuropharmacology; neuroprotectants; neurotoxicology; peptides; pharmacokinetics; protein protein interaction; receptor coupling; stroke; stroke therapy; tissue /cell culture; trauma

DESCRIPTION (provided by applicant): My goal is to find a treatment for stroke and CNS injury. Such injuries are partly mediated by synaptic glutamate receptors, which are also essential for CNS function. Curtailing synaptic function with glutamate antagonists is harmful and is a failed approach to treating stroke in humans. We have shown that toxic glutamatergic signals are restricted to distinct pathways, indicating that they might be blocked selectively, without affecting essential synaptic activity. This grant pursues our discovery of the molecular mechanism for neurotoxic signaling, which depends on NMDA receptor (NMDAR) interactions with submembrane scaffolding proteins. A key interaction is that of NMDARs with the scaffolding protein PSD-95. We have suppressed neuronal PSD-95, which uncoupled NMDARs from nitric oxide synthase, an enzyme tethered to NMDARs by PSD-95. This blocked NMDAR toxicity without blocking synaptic activity. More recently, using cell-permeant peptides that disrupt NMDAR/PSD-95 coupling, we treated stroke in animals. The treatment reduced focal ischemic brain damage in rats and improved their neurological outcome without blocking synaptic function. Our approach avoids the negative consequences of blocking NMDARs and may constitute a practical stroke therapy. We propose to pursue this promising approach further. In AIM 1 we will determine the mechanism of action of the therapeutic molecules that we discovered. In AIM 2 we will focus on the therapeutic limits (therapeutic window, duration of effect, neurobehavioral consequences) and toxicity of treating stroke and CNS trauma by dissociating NMDAR/ PSD-95 interactions. In AIM 3 we will identify novel therapeutic targets for neurological disease based on downstream interactions of PSD-95. The results will provide knowledge on mechanisms of disease and synaptic function, and validate a stroke treatment with the future intention of proceeding to human trials.

描述（由申请人提供）：我的目标是找到中风和中枢神经系统受伤的治疗方法。这种损伤部分是由突触谷氨酸受体介导的，这对于CNS功能也是必不可少的。用谷氨酸拮抗剂削减突触功能是有害的，是治疗人类中风的失败方法。我们已经表明，有毒的谷氨酸能信号仅限于不同的途径，表明它们可能被选择性地阻塞，而不会影响基本的突触活动。该赠款追求我们发现神经毒性信号传导的分子机制，该机制取决于NMDA受体（NMDAR）与枝骨支架蛋白的相互作用。一个关键的相互作用是NMDAR与脚手架蛋白PSD-95的相互作用。我们已经抑制了神经元PSD-95，该神经元从一氧化氮合酶中取消了NMDAR，这是一种由PSD-95束缚在NMDAR的酶。这阻断了NMDAR的毒性而不会阻止突触活动。最近，我们使用破坏NMDAR/PSD-95耦合的细胞 - 磨损肽，我们在动物中处理了中风。该治疗可减少大鼠局灶性缺血性脑损伤，并改善其神经系统损伤，而不会阻止突触功能。我们的方法避免了阻止NMDAR的负面后果，并且可能构成实用的中风疗法。我们建议进一步追求这种有希望的方法。在AIM 1中，我们将确定我们发现的治疗分子的作用机理。在AIM 2中，我们将通过分离NMDAR/ PSD-95相互作用来关注治疗限制（治疗窗口，效果持续时间，神经行为后果）和治疗中风和中枢神经系统创伤的毒性。在AIM 3中，我们将根据PSD-95的下游相互作用来确定神经疾病的新型治疗靶标。结果将提供有关疾病和突触功能机制的知识，并验证中风治疗，并以未来进行人体试验的意图。