Dr. Matthew Pearn has established himself as a promising researcher in the field of anesthetic-mediated neurotoxicity and axonal transport. He has secured and completed a two year FAER grant, investigating the role of RhoGTPase signaling, growth cone (GC) collapse, and axonal transport on anesthetic related neurotoxicity. This NIH K08 proposal extends his research, investigating the role of caveolin-1 (Cav1) on anesthetic-mediated neurotoxicity. The K08 Award will provide Dr. Pearn with the funding and protected time needed to accomplish the following goals: (1) to become an expert in the study of Cav1 biology, (2) to further advance his scientific writing and increase the volume of first author manuscripts, (3) to learn lab management and leadership skills, (4) to successfully acquire independent funding, and (5) to develop into a independent clinician-scientist. To accomplish these goals, Dr. Pearn has assembled a mentoring team comprised of Dr. Hemal Patel and Dr. Piyush Patel. Growth cone collapse and axonal transport is recognized as being critical for neuronal development and cognition. Both GC morphology and axonal transport are influenced by actin dynamics, which it turn are influenced by RhoGTPase signaling. Dr. Pearn has shown that neonatal neurons exposed to propofol (PPF) have increased RhoA activation relative to Rac1/Cdc42, along with GC collapse, impaired axonal transport, altered neuronal circuits, and cognitive deficits. Balancing RhoGTPase activity using a pharmacologic inhibitor of RhoA activation (i.e. TAT-C3) prior to propofol exposure ameliorates neurotoxicity. What is it about mature neurons that makes them less susceptible to neurotoxicity? Caveolin-1 is a membrane scaffolding protein that regulates and balances RhoGTPase signaling. Caveolin-1 expression increases with neuronal maturation. Dr. Pearn's K08 preliminary data suggests Cav1 plays a critical role in susceptibility to anesthetic-mediated neurotoxicity. When neonatal neurons are transfected with a viral vector to increase Cav1 expression, there is protection against PPF mediate alterations in RhoGTPase signaling, GC collapse, and axonal transport. Dr. Pearn will explore how Cav1 regulates RhoGTPase signaling in the presence of PPF (AIM 1). Furthermore, he will explore how Cav1 expression influences GC morphology and axonal transport (AIM 2), along with neuronal circuit connectivity and cognition (AIM 3). These findings may reveal how Cav1 protects against toxicity. As such, will identify potential therapeutic targets and biomarkers that predict susceptibility to anesthetic-mediated neurotoxicity.
/Public Health Relevance: Improving our understanding as to why neurons are susceptible and/or protected from anesthetic-mediated neurotoxicity is critical in identifying molecular targets that can aid in the development of both therapeutic interventions and biomarker assays should toxicity prove relevant in humans.
