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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：
10747258
负责人：
Bingren Hu
金额：
$ 15.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10747258
关键词：
Affect American Animals BIRC4 gene Basic Science Brain Injuries Brain Ischemia Cell Survival Clinical Research Complex Disease Evaluation Failure Female Gene Expression Profile Genes Golgi Apparatus Guidelines Heat-Shock Proteins 70 Hydrophobicity Infusion procedures Internal Ribosome Entry Site Intervention Intraperitoneal Injections Ischemia Ischemic Brain Injury Ischemic Stroke Knowledge Measures Mediating Messenger RNA Mitochondria Modeling Molecular Molecular Chaperones Molecular Target Neurologic Neurons Normal Cell Organelles Pathologic Pathway interactions Peptide Initiation Factors Peptides Play Program Development Proteins Quality Control Reperfusion Injury Reperfusion Therapy Reproducibility Research Role Solid Source Stress Stroke Structure System Testing Therapeutic Agents Translation Initiation Translations Transportation Ubiquitin United States National Institutes of Health age group brain cell clinical translation clinically relevant design drug development inhibitor male mitochondrial membrane nervous system disorder neuron loss neuroprotection new technology novel novel therapeutic intervention pharmacologic polypeptide prevent programs therapeutic target therapeutically effective

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.

中风是一种影响数百万美国人的毁灭性疾病。然而,大多数