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.