# Regulatory microRNAs-mediated cerebrovascular protection and traumatic braininjury

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Traumatic brain injury (TBI) is a major medical concern in service personnel and veterans as currently no
therapy is available to alleviate post-trauma neurological deficits. The blood-brain barrier (BBB) provides a
dynamic interface to separate the brain from the circulatory system, maintaining a stable brain
microenvironment. As a major component of the BBB, brain microvascular endothelial cells (BMECs), together
with intercellular tight junctions (TJs), play a dominant role in modulating BBB integrity and paracellular
permeability1. Accumulating evidence has demonstrated that BBB breakdown after TBI promotes a devastating
cascade of events such as transmigration of peripheral immune cells, cerebral inflammatory responses, edema,
and hemorrhagic transformation, contributing to secondary injury in neurotrauma. Thus, it is necessary to
identify mechanisms and develop effective therapeutic strategies that protect BBB integrity and prevent
permanent brain damage after TBI.
 MicroRNAs (miRs) function as a major class of small non-coding RNAs that negatively modulate protein
expression. In addition to their critical role in various biological processes, miRs have also been implicated in a
variety of human neurological diseases. We and others have shown the involvement of miRs in the
pathogenesis of TBI. However, the functional significance and molecular mechanisms of miR molecules in
regulating cerebrovascular pathogenesis, in particular BBB disruption/dysfunction, and resultant long-term
neurological outcomes are poorly understood in TBI.
 The miR-15a/16-1 cluster is the first identified miR group associated with human carcinogenesis.
Dysregulated plasma miR-15a/16-1 levels have been found in TBI individuals, showing great potential as
useful biomarkers in clinical diagnosis and prognosis. Interestingly, molecular inhibition of miR-15a/16-1 levels
has been shown to protect against myocardial infarction (MI) and ischemic brain injury. Therefore, American
and European pharmaceutical companies consider the miR-15a/16-1 cluster as one of the most important miR
targets to develop miR-based drugs for the treatment of MI.
 In our recent preliminary studies, we have shown that expression of the miR-15a/16-1 cluster is
selectively increased in the mouse cerebral vasculature after TBI. Of note, endothelial cell (EC)-selective miR-
15a/16-1 genetic deficiency leads to reduced BBB leakage, and less neuronal loss, white matter (WM) injury,
and neurobehavioral impairments in mice after TBI. We also found that the miR-15a/16-1 cluster can bind to
the 3’-UTRs of major BBB tight junctions, brain-enriched Claudins, and inhibit their translation, and genetic
silencing or deletion of the miR-15a/16-1 cluster significantly increased endothelial or cerebral expression of
claudins. These findings have provided the basis for our Central Hypothesis that genetic deletion of
vascular miR-15a/16-1 attenuates BBB disruption and subsequent pathological cascades after TBI,
thereb...

## Key facts

- **NIH application ID:** 10721359
- **Project number:** 5I01BX005750-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Kejie Yin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721359

## Citation

> US National Institutes of Health, RePORTER application 10721359, Regulatory microRNAs-mediated cerebrovascular protection and traumatic braininjury (5I01BX005750-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10721359. Licensed CC0.

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