During the first few hours after ischemic stroke, neurons can be rescued by administering anti-apoptotic drugs. This represents an important therapeutic opportunity and thus there is a compelling need to develop novel, clinically effective drugs to target these processes. In searching for novel pharmacological agents for the treatment of stroke, Drs. Martins and Ferchmin discovered a cembranoid compound 4R and demonstrated its neuroprotective effect in vitro. Recently, these findings were extended with the demonstration that 4R also can function as an effective neuroprotective agent in vivo. The present application proposes to build on these exciting findings and expand our work on the mechanism of action of this drug, which represents a new class of compounds with neuroprotective effect against ischemia. The application will test the hypothesis that the neuroprotective effect of 4R involves Akt, a well known anti-apoptotic and anti-inflammatory protein. Specifically, we hypothesize that 4R promotes neuroprotection by activating Akt, which leads to an inhibition of apoptosis, and suppresses inflammation by inhibiting cytokine release. This project, led by Dr. Martins and co-mentored by Drs. Ferchmin and Ford, will contribute to the expansion of our program to translational research. At the same time, scientific interactions between Dr. Martins and other Pis in the SNRP community, whose research is more heavily focused on mechanistic approaches in basic neuroscience, will help Dr. Martins to develop mechanistic approaches in his lab and thus contribute to his professional development Thus, this project aims to advance professional development of a junior faculty from an underrepresented group who is developing a highly significant line of translational neuroscience research focused on neuroprotection against stroke. The project is designed to allow Dr. Martins to collect preliminary data for a competitive U01 type application to the National Institute of Health.
|Vasin, Alexander; Zueva, Lidia; Torrez, Carol et al. (2014) Synapsin regulates activity-dependent outgrowth of synaptic boutons at the Drosophila neuromuscular junction. J Neurosci 34:10554-63|
|Ferchmin, P A; Andino, Myrna; Reyes Salaman, Rebeca et al. (2014) 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration. Neurotoxicology 44:80-90|
|Feliciano, Pedro; Andrade, Rodrigo; Bykhovskaia, Maria (2013) Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the hippocampus. J Neurosci 33:18319-30|