MicroRNA Therapeutics for Traumatic Brain Injury

MicroRNA 治疗创伤性脑损伤

• 批准号: 10093166
• 负责人: Jeff Dazhi Liu
• 金额: $ 50.39万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/10093166
• 关键词: 3' Untranslated Regions; Acute; Address; Aftercare; 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; Gene Proteins; Genes; Hippocampus (Brain); Human; IL2 gene; Impaired cognition; In Vitro; Infiltration; Inflammation; Intravenous; Intraventricular; Lateral; Leukocytes; Liposomes; Liquid substance; Literature; MAPK8 gene; Malignant Neoplasms; Mediating; MicroRNAs; Microglia; Modeling; Neurons; Neutrophil Infiltration; Oligonucleotides; Oncogene Activation; Oncogenes; Outcome; Pathologic; Pathway interactions; Percussion; Peripheral; Phosphotransferases; Play; Rattus; Research Personnel; Role; Route; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Translating; Traumatic Brain Injury; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Work; base; behavioral outcome; blood-brain barrier disruption; brain cell; cognitive function; disability; drug development; genome sequencing; improved; improved outcome; in vivo; inhibitor/antagonist; injured; kinase inhibitor; monocyte; neuron loss; neurotensin mimic 2; novel; prevent; response; roscovitine; sex; therapeutic miRNA; v-src Oncogenes; whole genome; young adult

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.

积累的证据表明，在癌症中广泛研究的癌基因/激酶可以是 杠杆治疗创伤性脑损伤（TBI）。证据包括：1）癌基因/激酶（例如SRC，岩石， TBI之后，ERK，CDK，其他）被激活； 2）激活癌基因/激酶不仅引起神经元死亡 通过细胞周期重新进入成熟的神经元，但也介导白细胞浸润和注射，从而导致 在TBI之后的BBB中断中； 3）致癌基因/激酶抑制剂可以改善TBI结果，例如SRC 抑制剂（PP2），岩石抑制剂（Y-27632），ERK抑制剂（PD98059），CDK抑制剂（Roscovitine）等。 在此赠款应用中，调查人员假设升高单个肿瘤抑制剂 microRNA（miR）减少多种癌基因/激酶将改善TBI结果。调查人员 靶向肿瘤抑制器Micronra-125b（miR-125b）作为TBI治疗的候选者，因为：1） PILOT miR表达研究表明，miR-125b是明显改变的前两个miRNA之一 TBI和ICH之后的血液； 2）miR-125b减少了多种肿瘤基因（例如MKNK2，Alpk3，neu1， BAP1，E2F，JNK，ERK，其他）如Mir-Target算法（TargetScan）所预测的 研究人员先前显示的SRC在改善TBI结果中起着至关重要的作用。这 初步治疗研究表明，miR-125b模拟（2.4mg/kg，静脉注射，i.v.）和/或 （0.24mg/kg，脑内室内，i.c.v.）可以在急性阶段（24小时）和 在TBI之后，在以后的时间（11-15天）促进认知功能。 研究人员将机械研究重点放在本提案中的外围效应上，如i.v.治疗 更像人类。使用整个基因组测序，研究人员确定了前四个miR- 125b靶基因（MKNK2，Alpk3，neu1，bap1）在miR-125b模拟治疗后血液中降低 在TBI之后。请注意，所有四个最高反应性基因均为致癌基因/激酶。初步机械 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寡素（MOS） - miR125b - MKNK2阻止了miR-125b与MKNK2的3'UTR的结合。而且，他们 将证明MO – MIR125B – MKNK2/ALPK3/neu1/bap1体内可防止miR-125b模拟诱导的降低 这些靶基因（白细胞，血小板），内皮细胞和脑细胞（神经元，星形胶质细胞， 小胶质细胞）在TBI之后，因此阻止了miMIMIM MIMIC产生的治疗作用。 总而言之，该提案将表明miR-125b模拟物具有外围和中心效应 通过降低miR-125b靶基因/激酶（MKNK2，ALPK3，NEU1，BAP1）来改善TBI结果。这 研究将有助于TBI领域的癌基因/激酶病理生理学的文献。联合用途 i.v. miR-125b模拟于治疗大鼠TBI的脂质体是新颖的，可以翻译成治疗人类TBI。