Novel anti-NPC aggregation strategy against brain ischemia-reperfusion injury

抗脑缺血再灌注损伤的新型抗NPC聚集策略

• 批准号: 9311808
• 负责人: Bingren Hu
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311808
• 关键词: Affect; Age-Months; American; Animals; BIRC4 gene; Basic Science; Brain Injuries; Brain Ischemia; Cell Survival; Complex; Disease; Evaluation; Failure; Female; Gene Expression Profile; Genes; Golgi Apparatus; Guidelines; Heat-Shock Proteins 70; Hydrophobicity; Infusion procedures; Injection of therapeutic agent; Internal Ribosome Entry Site; Intervention; Intraperitoneal Injections; Ischemia; Ischemic Stroke; Knowledge; Measures; Messenger RNA; Mitochondria; Modeling; Molecular; Molecular Chaperones; Molecular Target; Neurologic; Neurons; Normal Cell; Organelles; Pathologic; Pathway interactions; Peptide Initiation Factors; Peptides; Pharmacology; Play; Program Development; Proteins; Quality Control; Reperfusion Injury; Reperfusion Therapy; Reproducibility; Role; Solid; Source; Stress; Stroke; Structure; System; Testing; Therapeutic Agents; Translation Initiation; Translations; Transportation; Treatment Efficacy; United States National Institutes of Health; age group; base; brain cell; clinical translation; clinically relevant; design; drug development; inhibitor/antagonist; intraperitoneal; male; mitochondrial membrane; nervous system disorder; neuron loss; neuroprotection; new technology; novel; novel therapeutic intervention; polypeptide; prevent; therapeutic target

Project Summary: Stroke is a devastating disease affecting millions of Americans. However, most prior stroke drug development programs were unsuccessful for a variety of reasons. One of them may be that the appropriate therapeutic targets remain to be identified. Our recent studies show that massive aggregation of nascent peptide chains (NPCs) may play a role in ischemia-reperfusion injury. NPCs, i.e., newly or partially synthesized polypeptides, are the major source of unfolded proteins and highly prone to toxic aggregation in a normal cell. To avoid toxic aggregation, cellular NPCs must be protected by molecular chaperones. Our latest studies show that brain ischemia damages multiple groups of molecular chaperones, resulting in massive NPC aggregation with the ER, Golgi, and mitochondria structures during reperfusion. The amounts of NPC aggregate-associated organelles increase progressively until delayed neuronal death occurs after brain ischemia. Although our studies strongly support this hypothesis, this remains a largely unsettled issue because no study has ever shown that blocking of NPC aggregation protects the brain from ischemia-reperfusion injury, and molecular target(s) for managing NPC aggregation remain to be identified. Furthermore, it may be vitally important to study the translation ability of these basic science discoveries. We have recently found that the newly developed eIF4E inhibitors have strong anti- NPC aggregation effects and offer robust neuroprotection in animal ischemia models. Aim 1 is designed for proof of concept studies of the novel hypothesis that massive NPC aggregation plays a key role in ischemia-reperfusion injury, and eIF4E is a new and best therapeutic target against NPC aggregation. This new hypothesis has not been tested previously, but is essential to develop new therapeutic strategies against ischemia-reperfusion injury. In this Aim, we will use newly developed initiation inhibitors and several new technologies: (i) to identify the best therapeutic target(s) against massive NPC aggregation; and (ii) to study whether the novel anti-NPC aggregation strategy protects the protein quality control systems, and prevents multiple organelle failure after brain ischemia. Aim 2 proposes studies of the clinical translation ability of the new anti-NPC aggregation strategy. This Aim is based on solid new evidence that postischemic and intraperitoneal injection of eIF4E inhibitors offers robust neuroprotection in animal brain ischemia models. We will initially identify the best therapeutic target(s), and then carry out comprehensive studies of the neuroprotection following the STAIR criteria and the new NIH guideline of Rigor and Reproducibility including: (i) two clinically relevant focal ischemia models; (ii) both male and female, (iii) 3- and 12 month age groups, (iv) post-ischemic treatment, (v) 7- and 28-day endpoints, and (vi) performing thorough molecular, pathological and neurological evaluations. These studies will capture many clinically relevant aspects of the mechanisms and neuroprotection.

项目摘要：中风是一种影响数百万美国人的毁灭性疾病。但是，大多数 出于各种原因，先前的中风药物开发计划未能成功。其中之一可能是 适当的治疗靶标仍有待确定。我们最近的研究表明，大量 新生肽链（NPC）的聚集可能在缺血 - 再灌注损伤中起作用。 NPC，即 新近或部分合成的多肽是未折叠蛋白的主要来源，高度容易 正常细胞中的有毒聚集。为避免有毒聚集，必须保护细胞NPC 分子伴侣。我们的最新研究表明，脑缺血会损害多组分子 伴侣，在ER，高尔基体和线粒体结构中导致大量NPC聚集 再灌注。 NPC聚合相关细胞器的量逐渐增加直到延迟 神经元死亡发生在脑缺血后。尽管我们的研究强烈支持这一假设，但 仍然是一个不安的问题，因为没有研究表明NPC聚合的阻止 保护大脑免受缺血 - 重新灌注损伤和用于管理NPC聚集的分子靶标 仍有待确定。此外，研究这些基本的翻译能力可能至关重要 科学发现。我们最近发现，新开发的EIF4E抑制剂具有很强的抗抗 NPC聚集作用并在动物缺血模型中提供鲁棒的神经保护作用。 AIM 1是设计的 为了证明对新假设的概念研究，大规模NPC聚集起着关键作用 缺血 - 重新灌注损伤，EIF4E是针对NPC聚集的新的，最佳的治疗靶标。这 以前尚未对新假设进行测试，但对于制定新的治疗策略至关重要 反对缺血 - 重新灌注损伤。在此目标中，我们将使用新开发的启动抑制剂， 几种新技术：（i）确定针对大规模NPC聚合的最佳治疗靶标； （ii）研究新型抗NPC聚集策略是否保护蛋白质质量控​​制 系统，并防止脑缺血后多个细胞器衰竭。 AIM 2提出了临床的研究 新抗NPC聚合策略的翻译能力。这个目标是基于可靠的新证据 EIF4E抑制剂的疾病后和腹膜内注射可在动物脑中提供强大的神经保护作用 缺血模型。我们最初将确定最佳的治疗靶点，然后进行全面实现 遵循楼梯标准和新的严格NIH指南的神经保护的研究 可重复性包括：（i）两个临床相关的局灶性缺血模型； （ii）男性和女性，（iii）3- 和12个月的年龄组，（iv）缺血后治疗，（v）7天和28天终点，以及（vi）执行 彻底的分子，病理和神经系统评估。这些研究将在临床上捕获许多 机制和神经保护的相关方面。