Current Research Projects
The role of neuroinflammation in traumatic brain injury
Traumatic brain injury (TBI) is a leading cause of death and disability, affecting millions of Americans each year. Injury occurs in two phases: (1) the initial impact, and (2) the various inflammatory processes that occur after the injury. While changes such as consistent seatbelt use and improved helmet design has helped reduce initial injury severity, relatively little progress has been made in reducing the harmful inflammation that plays a critical role in patient outcome hours to weeks after injury. We are interested in innate immunity regulatory proteins that control interferon signaling after TBI that facilitate cellular changes in the brain and contribute to inflammation. What major neurinflammatory pathways activate resident central nervous system cells like microglia and control peripheral immune cell infiltration to the contused brain? How is interferon signaling harmful to neurons after brain injury?
Interorganelle crosstalk between mitochondria quality control and mitosis
Mitochondria perform oxidative phosphorylation to generate ATP for a majority of the cells in the body. The accumulation of damaged or dysfunctional mitochondria contribute to a wide range of human diseases. Mitophagy is a quality control process that eliminates and recycles damaged mitochondria to prevent their accumulation. A majority of studies focus on how mitophagy defects affect post-mitotic cells because the first identified autosomal recessive mutations in mitophagy genes caused neurodegenerative diseases such as Parkinson’s. However, it is now clear that many other cell types have high levels of mitophagic activity; yet, we do not understand the importance or impact of mitophagy in these contexts. For example, stem cells display high levels of mitophagy, divide continuously throughout their lifespan, and possibly use mitophagy as a mechanism to ensure daughter cells receive healthy mitochondria. Towards this goal, our findings support that mitophagy and cell division are intimately linked by a required interorganelle signaling kinase that translocates to either mitochondria or centrosomes to activate either cell process. The broad implications of this work will elucidate why mitophagy genes are mutated in other complex diseases such as cancer, provide insight into how mitochondrial dysfunction affects stem cells contributing to neurodevelopmental and cognitive disorders, and define fundamental signaling interactions between organelles to deepen our understanding of how cells globally respond to dysfunctional mitochondria.
How antiviral drugs impact mitochondrial activity
Antiviral nucleoside analogues are a type of broad-spectrum medication used to prevent viral replication. Only one FDA approved treatment for COVID-19 is a nucleoside analogue and was used under FDA emergency directive to reduce hospitalization times to treat patients infected with the SARS-CoV-2. However, in the past, FDA approved antiviral ribonucleoside analogues used to control infection during the US HIV/AIDS epidemic were shown years later to cause mitochondrial DNA mutations, mitochondrial dysfunction, myopathies, and cause chronic side effects to treated patients. This study addresses whether these novel antiviral ribonucleoside analogues (Remdesivir) currently the only FDA approved mediation or (N4-Hydroxycytidine) in Phase II/III clinical trials for COVID-19 affect mitochondrial DNA and mitochondrial function causing cellular and tissue dysfunction.