ABSTRACT
Traumatic brain injury (TBI) afflicts over 1.7 million persons per year in the U.S. alone, resulting in
substantial economic burden annually. It is well known that the mechanical insult from TBI initiates
immediate cellular death (i.e. primary injury) and stimulates a broad range of complex deleterious signaling
cascades (i.e. secondary injury). Altered gene regulation is at the crux of the secondary injury signaling cascade,
which generates silencing of genes critical for cell survival, neural plasticity, and homeostatic maintenance, as
well as activation of inflammatory and cell death genes. Our long-term goal is to develop clinically translatable
therapeutics that minimize neuroinflammation following a TBI. Here, our primary objective is to inhibit
deleterious epigenetic modifications that occur following TBI through nanoparticle based delivery of small
molecule drugs that inhibit histone deacetylases (HDACs), which we predict will alleviate neuropathology
toward functional recovery in a murine model. Acetylation of histones is one epigenetic modification that
enables relaxation of chromatin to facilitate gene expression. In contrast, HDACs remove acetylation points,
allowing for chromatin compaction and gene silencing. After TBI, HDAC levels are markedly increased. Thus,
HDACs are a key cellular target contributing to the pro-inflammatory and anti-neuroplastic microenvironment
that characterizes the second phase injury response in TBI. Recently, numerous preclinical studies in TBI have
shown that early administration of HDAC inhibitors (HDACis) significantly decreases the neurological damage,
as evidenced by increased neural survival, decreased inflammatory markers, and improved functional
outcomes. However, a key limitation in translating HDACi treatment to the clinic is the need for
supratherapuetic dosing, which contributes to undesired systemic side effects (i.e. neuropathic pain). Recently,
the Sirianni group developed a novel strategy to enable very high loading of acidic HDACis within polymeric
nanoparticles composed of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG). Importantly, the Stabenfeldt
group has demonstrated a transient window inside 12hrs after TBI where marked NP accumulation occurs
within the injury penumbra; these studies identify a unique opportunity for synergistically enhancing NP
delivery by timing treatment appropriately after injury. Combining these key innovations will enable evaluation
of HDACi NPs as an intervention for TBI. Our specific aims are to (1) develop a library of HDACi NPs directed
at minimizing neuroinflammation, (2) evaluate the impact HDACi NP intervention has on minimizing aberrant
pathology following TBI toward improving functional recovery. We expect that completion of these aims will
simultaneously advance HDACi as a therapeutic strategy and improve our understanding of NP delivery in TBI.