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MicroRNA Therapeutics for Traumatic Brain Injury

MicroRNA 治疗创伤性脑损伤

基本信息

批准号：
10565688
负责人：
Jeff Dazhi Liu
金额：
$ 50万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565688
关键词：
3&apos Untranslated Regions Acute Address Algorithms Animal Model Applications Grants Astrocytes Attenuated Binding Binding Sites Blood Blood Cells Blood Platelets Brain Brain Injuries Cause of Death Cell Cycle Clinical Trials Cognitive deficits Data Dose Drug Delivery Systems Endothelial Cells Endothelium Enzymes FDA approved Failure Functional disorder Genes Hippocampus Human IL2 gene Impaired cognition In Vitro Infiltration Inflammation Intravenous Intraventricular Lateral Leucocytic infiltrate Leukocytes Liposomes Liquid substance Literature MAPK8 gene Malignant Neoplasms Mediating MicroRNAs Microglia Modeling Neurons Oligonucleotides Oncogene Activation Oncogenes Outcome Pathologic Pathway interactions Percussion Peripheral Phosphotransferases Play Proteins Rattus Research Personnel Role Route T cell infiltration T-Lymphocyte Testing Therapeutic Therapeutic Effect Therapeutic Studies Tissues Translating Traumatic Brain Injury Tumor Suppressor Proteins Work behavioral outcome blood-brain barrier disruption brain cell cognitive function disability drug development genome sequencing improved improved outcome in vivo inhibitor injured kinase inhibitor monocyte neuron loss neutrophil novel prevent response roscovitine sex therapeutic miRNA translational potential v-src Oncogenes whole genome young adult

项目摘要

Accumulating evidence shows oncogenes/kinases that have been widely studied in cancers can be leveraged to treat traumatic brain injury (TBI). The evidence includes: 1) oncogenes/kinases (e.g., Src, ROCK, ERK, CDK, others) are activated after TBI; 2) activation of oncogenes/kinases not only cause neuronal death via cell cycle re-entry in mature neurons, but also mediate leukocyte infiltration and inflammation which results in BBB disruption after TBI; and 3) oncogenes/kinases inhibitors can improve TBI outcome, such as Src inhibitor (PP2), ROCK inhibitor (Y-27632), ERK inhibitor (PD98059), CDK inhibitor (Roscovitine), and others. In this grant application, the investigators hypothesized that elevating a single tumor suppressor microRNA (miR) to decrease multiple oncogenes/kinases will improve TBI outcomes. The investigators targeted tumor suppressor microNRA-125b (miR-125b) as a candidate for TBI therapeutics, because: 1) the pilot miR expression study showed that miR-125b is one of the top two miRNAs that significantly altered in blood after both TBI and ICH; and 2) miR-125b decreases multiple oncogenes (e.g., Mknk2, Alpk3, Neu1, Bap1, E2F, JNK, ERK, others) as predicted by miR-target algorithm (TargetScan), in addition to the oncogene Src which the investigators have previously shown plays an critical role in improving TBI outcome. The preliminary therapeutic studies demonstrate that miR-125b mimic (2.4mg/kg, intravenously, i.v.) and/or (0.24mg/kg, intracerebroventricularly, i.c.v.) can improve pathological outcome at acute stage (24 hr) and promote cognitive function at later times (11-15 days) after TBI. The investigators focus the mechanistic study on peripheral effects in this proposal, as i.v. treatment is more translatable to humans. Using whole genome sequencing, the investigators identify the top four miR- 125b target genes (Mknk2, Alpk3, Neu1, Bap1) that are decreased in blood after miR-125b mimic treatment after TBI. Note that all of the four top responsive genes are oncogenes/kinases. The preliminary mechanistic study data show: 1) miR-125b binds to the 3’ untranslated regions (3’UTR) of Mknk2, Neu1 and Bap1; and 2) Morpholino Oligos (MOs)–miR125b–Mknk2 blocks the binding of miR-125b to 3’UTR of Mknk2. Moreover, they will prove that MO–miR125b–Mknk2/Alpk3/Neu1/Bap1 in vivo prevents miR-125b mimic-induced decrease of these target genes in blood cells (leucocytes, platelets), endothelium, and brain cells (neurons, astrocytes, microglia) after TBI, and thus blocks the therapeutic effects produced by miR-125b mimic after TBI. In summary, this proposal will show that miR-125b mimic has both peripheral and central effects to improve TBI outcome via decreasing miR-125b target oncogenes/kinases (Mknk2, Alpk3, Neu1, Bap1). This study will contribute to the literature of oncogenes/kinases pathophysiology in the TBI field. The combined use of i.v. miR-125b mimic and liposomes to treat TBI in rats is novel, and can be translated to treat human TBI.

越来越多的证据表明，在癌症中得到广泛研究的癌基因/激酶可以用于治疗创伤性脑损伤（TBI）。证据包括：1) 癌基因/激酶（例如，Src、ROCK、 ERK、CDK等）在TBI后被激活； 2）癌基因/激酶的激活不仅导致神经元死亡通过成熟神经元的细胞周期重新进入，还介导白细胞浸润和炎症，从而导致 TBI 后 BBB 中断； 3) 癌基因/激酶抑制剂可以改善 TBI 的结果，例如 Src 抑制剂（PP2）、ROCK抑制剂（Y-27632）、ERK抑制剂（PD98059）、CDK抑制剂（Roscovitine）等。在这项拨款申请中，研究人员假设提高单一肿瘤抑制因子的水平减少多种癌基因/激酶的 microRNA (miR) 将改善 TBI 的结果。调查人员靶向肿瘤抑制基因 microNRA-125b (miR-125b) 作为 TBI 治疗的候选者，因为：1) 初步 miR 表达研究表明，miR-125b 是在 miR-125b 中显着改变的两个 miRNA 之一。 TBI 和 ICH 后的血液； 2) miR-125b 减少多种癌基因（例如 Mknk2、Alpk3、Neu1、除癌基因外，miR-target 算法 (TargetScan) 预测的 Bap1、E2F、JNK、ERK 等研究人员之前已经证明 Src 在改善 TBI 结局方面发挥着关键作用。这初步治疗研究表明，miR-125b 模拟物（2.4mg/kg，静脉注射，i.v.）和/或（0.24mg/kg，脑室内，i.c.v.）可以改善急性期（24小时）和促进 TBI 后（11-15 天）的认知功能。研究人员在该提案中将机制研究重点放在外围效应上，如 i.v.治疗更适合人类。通过全基因组测序，研究人员确定了前四种 miR- miR-125b 模拟物治疗后血液中的 125b 靶基因（Mknk2、Alpk3、Neu1、Bap1）减少 after TBI.请注意，所有四个最敏感的基因都是癌基因/激酶。初步机制研究数据显示：1) miR-125b 与 Mknk2、Neu1 和 Bap1 的 3' 非翻译区 (3'UTR) 结合；和 2) Morpholino Oligos (MOs)–miR125b–Mknk2 阻断 miR-125b 与 Mknk2 3’UTR 的结合。而且，他们将证明 MO–miR125b–Mknk2/Alpk3/Neu1/Bap1 在体内可防止 miR-125b 模拟物诱导的这些靶基因存在于血细胞（白细胞、血小板）、内皮细胞和脑细胞（神经元、星形胶质细胞、 TBI 后的小胶质细胞），从而阻断 TBI 后 miR-125b 模拟物产生的治疗作用。总之，该提案将表明 miR-125b 模拟物具有外周和中枢作用通过减少 miR-125b 靶癌基因/激酶（Mknk2、Alpk3、Neu1、Bap1）改善 TBI 结局。这研究将为 TBI 领域的癌基因/激酶病理生理学文献做出贡献。 The combined use of i.v. miR-125b 模拟物和脂质体治疗大鼠 TBI 是新颖的，并且可以转化为治疗人类 TBI。