Traumatic brain injury (TBI) triggers delayed biochemical changes, including chronic neuroinflammation, that contribute to tissue loss and neurological deficits. Similar to clinical TBI, we have shown that M1 (neurotoxic) microglia are chronically active for months-to-years following experimental TBI, contributing to progressive neurodegeneration. Our group was the first to demonstrate the ability of conventional orthosteric mGluR5 metabotropic glutamate receptor 5 (mGluR5) agonists to attenuate miR-155, a key M1-inducing microRNA (miR), negatively regulate the M1 phenotype, limit chronic microglial activation and reduce progressive neuronal loss, even when administered centrally at one month after TBI. Importantly, mGluR5 positive allosteric modulators (PAMs) not only attenuate M1 but also promote M2 (neuroprotective) microglia phenotypes after TBI. This is accomplished by combined action on key microRNA modulators of neuroinflammation, down-regulating miR-155 and up-regulating the M2-inducing miR-124. There is an urgent unmet need to identify selective targeted therapies to limit posttraumatic inflammatory neurodegeneration. Our central hypothesis is that selective mGluR5 PAMs have superior therapeutic effects than orthosteric agonists on neuroinflammation/neurodegeneration by concurrently attenuating both TBI-induced chronic M1 responses and promoting neuroprotective M2 responses; molecular interventions that target the underlying mechanisms and tip the miR-155/miR-124 balance in favor of miR-124 are neuroprotective. These hypotheses are supported by strong preliminary studies showing that mGluR5 PAMs lower miR-155, increase miR-124, reverse M1/M2 imbalance, as well as attenuate neuronal loss and neurological impairments following TBI. The proposed specific aims are: 1) Define the specific mGluR5 PAM (VU0360172) signaling intermediaries that are responsible for down-regulating M1 and up-regulating M2 microglia; 2) Determine the neuroprotective effects of delayed systemic treatment with mGluR5 PAMs on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments; and 3) Determine the neuroprotective effects of delayed molecular interventions targeting miR-155/-124 on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments.
These aims should support the following expected outcomes: neuroprotective effects of mGluR5 PAMs after TBI reflect, in part, reversing posttraumatic miR-155/miR-124 changes; that mGluR5 PAMs have robust neuroprotective effects even with delayed systemic administration; and that combined molecular modulation of miR-155 (down-regulation) and miR-124 (up-regulation) after TBI have additive neuroprotective effects. We expect to have an important positive impact by demonstrating the pathophysiological mechanisms underlying progressive neurodegeneration after TBI, and providing experimental support for late therapeutic interventions that alter M1/M2 balance.

Public Health Relevance

Traumatic brain injury (TBI) causes persistent neuroinflammation and progressive neurodegeneration; these changes are associated with motor deficits and cognitive decline. Here we propose to examine the mechanisms responsible for microglial activation in key brain centers by examining the role of mGluR5 as a modulator of neuroinflammation after TBI, which suppresses the M1 (neurotoxic) and induces the M2 (neuroprotective) microglia phenotype. We will test our hypothesis that stimulation of mGluR5 using novel positive allosteric modulators inhibits M1 pathways, including miR-155, and promotes M2 pathways, including miR-124; such actions serve to limit chronic neuroinflammation after TBI, leading to reduced neurodegeneration and improved neurological recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS037313-15A1
Application #
8964030
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
1999-02-03
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
15
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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