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.

项目概述：中风是一种毁灭性的疾病，影响着数百万美国人。然而，大多数 以前的中风药物开发计划由于各种原因都不成功。其中一人可能是 合适的治疗靶点仍有待确定。我们最近的研究表明，大规模的 新生肽链的聚集可能在缺血再灌注损伤中起一定作用。NPC，即， 新合成或部分合成的多肽，是未折叠蛋白质的主要来源，极易 正常细胞中的有毒聚集。为了避免有毒聚集，蜂窝NPC必须由 分子伴侣。我们最新的研究表明，脑缺血会损害多组分子 伴侣蛋白，导致鼻咽癌在内质网、高尔基体和线粒体结构中大量聚集 再灌流。鼻咽癌聚集相关细胞器的数量逐渐增加，直到延迟 脑缺血后会发生神经元死亡。尽管我们的研究有力地支持了这一假设，但这 仍然是一个在很大程度上悬而未决的问题，因为从来没有研究表明阻止鼻咽癌聚集 脑缺血再灌注损伤的保护作用及控制鼻咽癌聚集的分子靶点(S) 仍有待确认。此外，研究这些基础知识的翻译能力也是至关重要的 科学发现。我们最近发现，新开发的eIF4E抑制剂具有很强的抗肿瘤活性。 鼻咽癌聚集效应，并在动物缺血模型中提供强大的神经保护。AIM 1的设计 对于大量的鼻咽癌聚集在 EIF4E是一种新的抗鼻咽癌聚集的治疗靶点。这 新的假说以前没有被检验过，但对于开发新的治疗策略是必不可少的。 抗缺血再灌注损伤。在这一目标中，我们将使用新开发的启动抑制剂和 几项新技术：(I)确定对抗鼻咽癌大量聚集的最佳治疗靶点(S)； 以及(Ii)研究新的抗NPC聚集策略是否保护蛋白质质量控制 并防止脑缺血后的多细胞器衰竭。目标2建议临床研究 新的反NPC聚合策略的翻译能力。这一目标基于确凿的新证据，即 脑缺血后和腹腔注射eIF4E抑制剂对动物脑的强大神经保护作用 缺血模型。我们将初步确定最佳治疗靶点(S)，然后进行全面 楼梯标准和美国国立卫生研究院新指南下神经保护的研究 重复性包括：(I)两种临床相关的局灶性缺血模型；(Ii)男性和女性，(Iii)3- 和12个月年龄组，(4)缺血后治疗，(5)7天和28天终点，(6)进行 彻底的分子、病理和神经学评估。这些研究将捕捉到许多临床上的 机制和神经保护的相关方面。