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

基本信息

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
项目类别：
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

项目摘要

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。然而，大多数先前的中风药物开发计划因多种原因而失败。其中之一可能是适当的治疗靶点仍有待确定。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发挥作用。 NPC，即新的或部分合成的多肽，是未折叠蛋白质的主要来源，并且很容易发生正常细胞中的毒性聚集。为了避免毒性聚集，细胞 NPC 必须受到保护分子伴侣。我们的最新研究表明，脑缺血会损害多组分子分子伴侣，导致 NPC 在 ER、高尔基体和线粒体结构中大量聚集再灌注。 NPC聚集相关细胞器的数量逐渐增加直至延迟脑缺血后会发生神经元死亡。尽管我们的研究强烈支持这一假设，但仍然是一个很大程度上悬而未决的问题，因为没有研究表明阻止 NPC 聚集保护大脑免受缺血再灌注损伤，以及管理 NPC 聚集的分子靶点仍有待确定。此外，研究这些基础知识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- NPC 聚集效应并在动物缺血模型中提供强大的神经保护作用。设计目标1 大规模 NPC 聚集在其中发挥关键作用的新假设的概念验证研究缺血再灌注损伤，eIF4E是抗NPC聚集的新的最佳治疗靶点。这新假设之前尚未经过测试，但对于开发新的治疗策略至关重要抗缺血再灌注损伤。在这个目标中，我们将使用新开发的引发抑制剂和多项新技术：(i) 确定针对大规模鼻咽癌聚集的最佳治疗靶点； (ii) 研究新型抗 NPC 聚集策略是否可以保护蛋白质质量控制系统，并防止脑缺血后多种细胞器衰竭。目标 2 提出临床研究新的抗NPC聚合策略的翻译能力。这一目标基于可靠的新证据：缺血后和腹腔注射 eIF4E 抑制剂可为动物大脑提供强大的神经保护缺血模型。我们会初步确定最佳治疗靶点，然后进行综合治疗遵循 STAIR 标准和新的 NIH 严格和严格指南的神经保护研究重现性包括：（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、病理和神经学评估。这些研究将捕捉到许多临床机制和神经保护的相关方面。