Speaker at Global Conference on Pharmaceutics and Drug Delivery Systems 2018 - Joe E. Springer
University of Kentucky, United States
Title : Nanoparticle delivery of mitochondria-associated microRNA regulating inflammation in the central nervous system


Traumatic brain injury (TBI) is a leading cause of long-term impairments in higher cognitive function. Ongoing destructive secondary injury events occur minutes to days after the initial insult characterized by a cascade of pervasive biochemical and pathophysiological stressors including mitochondrial dysfunction, free radical-mediated oxidative damage, and inflammation. A rapid and sustained phase of mitochondrial dysfunction after TBI impacts a number of important cellular events. Our recent studies revealed that the levels of several mitochondria-associated miRNAs regulating inflammation (e.g., miR-146a) are altered early on after TBI at times that corresponds to a loss of mitochondrial function. Knowledge of the temporal changes in mitochondria associated miRNA levels after TBI provides an opportunity to target specific miRNA at specific time points. Two validated targets of miR-146a (TRAF6 and IRAK1) are thought to be involved in the differential expression of the M1 pro-inflammatory and M2 anti-inflammatory macrophage/microglia phenotypes. Recently, we employed a peptide-based miRNA nanoparticle delivery approach as a strategy to favor M2 microglia/macrophage expression and promote tissue repair following TBI. Specifically, we found that in vitro and in vivo nanoparticle delivery of miR-146a mimic reduced expression of TRAF6 and IRAK1, decreased expression of several pro-inflammatory markers (e.g., Marco, IL-6, and Nos2) and increased expression of anti-inflammatory markers (IL-4, Mrc1, and Arg1). The outcomes of our studies suggest a temporally dynamic interaction of miRNAs with mitochondria and point a potential role for mitochondria in directing the cellular function of specific miRNA regulating inflammatory responses in the central nervous system (CNS). Our studies also demonstrate the use of a peptide-based nanoparticle approach to effectively deliver miRNA mimics as a way to target specific miRNA activities following TBI and possibly other CNS-related injury events.

Audience take away:
• The audience will gain a better understanding of signaling events regulating inflammatory miRNA expression after traumatic brain injury.
• The ability to manipulate the activity of miRNAs regulating inflammation has therapeutic potential in the treatment of traumatic brain injury.
• Regulation of key mitochondria- associated inflammatory miRNA in response to CNS injury may be tissue and cell specific.
• Our current studies utilize microinjections of miR-146a containing nanoparticles directly into the CNS tissue, which is not clinically optimal. Therefore, identification of delivery strategies that obviate the need for direct injections into the CNS is a high priority.


Joe Springer is a Professor of Neuroscience and Interim Director of the Spinal Cord and Brain Injury Research Center at the University of Kentucky. His lab was one of the first to demonstrate the potential therapeutic potential of riluzole as a treatment for acute spinal cord injury (SCI) and riluzole is now in phase III clinical trials. His lab also was the first to characterize the molecular signaling events linking mitochondria associated caspase-dependent activation and apoptotic oligodendroglia cell death in SCI. Most recently, his lab is collaborating with Dr. Wangxia Wang, who is a recognized expert in miRNA biology to examine the role of mitochondria in regulating the cellular activity of inflammatory miRNA following traumatic brain injury.