SNRP Investigators and Collaborators
Neuroprotection of the Cembranoid 4R Compound Against Stroke
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 project builds on these exciting findings and expands our work on the mechanism of action of this drug, which represents a new class of compounds with neuroprotective effect against ischemia. The project tests 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.
SNRP PROJECT 2 Ramon Jorquera, Ph.D., PI Collaborator Dr. C.-F. Wu, University of Iowa
Regulation of Synaptic Vesicle Mobilization, Priming and Recycling by Complexin
Neuronal communications requires the availability of synaptic vesicles for neurotransmitter release. During his postdoctoral study, Dr. Jorquera demonstrated that complexin, a small cytosolic protein that binds the vesicle fusion complex, regulates vesicle availability in Drosophila, as well as vesicle trafficking between functional pools of synaptic vesicles. This is an exciting finding because it suggests a novel role for complexin in addition to its well defined function in the final steps of exocytosis. Because complexin dysfunction has been widely implicated in human diseases, including schizophrenia and Huntingtons, as well as cognitive dysfunction in the cortex and hippocampus, there is an important need to define the role of complexin in vesicle pool dynamics and in short-term plasticity. Defining the biological role of vesicle cycling in neural plasticity and complexin regulation in the brain represents a fundamental advance in our understanding of the biology of the synapse and neuronal communication. This is the focus of Dr. Jorquera’s project.SNRP PROJECT 3 Maria Bykhovskaia, Ph.D., PI Collaborator Dr. J. Troy Littleton, Massachusetts Institute of Technology
Activity-dependent Regulation of Synaptic Vesicle Abundance
Synaptic vesicle cycling is highly dynamic and plastic, and subtle disruptions in its regulation may contribute to severe neurological disorders, including schizophrenia, epilepsy, Huntington’s and Parkinson’s Disease. Although a number of molecular determinants of vesicle cycling at synaptic terminals have been identified, our understanding of how vesicle cycling contributes to plasticity remains sparse. Using the Drosophila neuromuscular junction (NMJ), the lab of Dr. Bykhovskaia has discovered a pathway of presynaptic enhancement that may enable a nerve terminal to sustain and enhance its activity upon intense stimulation. Specifically, it was found that vesicle abundance in synaptic boutons is regulated by activity, and that intense stimulation increases vesicle number in nerve terminals. Importantly, these results suggest a functional implication for this form of plasticity: enhanced activity upon a subsequent intense stimulation. This project employs a combination of molecular biology and genetics, live confocal imaging, and electron microscopy to unravel the mechanisms by which the terminal regulates its vesicle numbers in response to activity. Further, the project will test whether the phenomenon observed at the Drosophila glutamatergic synapse could be also detected in the mammalian central or peripheral synapses.