Gabriela C. Brailoiu, MD

Epidemiology of Infectious Diseases, University of Medicine and Pharmacy, Iasi, Romania

Society for Neuroscience

Jefferson College of Pharmacy, AACP Teacher of the Year – 2015-2016

Signaling mechanisms involved in the modulation of the blood-brain permeability. Blood-brain barrier (BBB), comprising of endothelial cells, pericytes and astrocytes, is essential for neuroprotection and cerebral homeostasis by regulating the transport of various molecules from the blood to the brain. Brain microvascular endothelial cells of the BBB form a tight monolayer with low paracellular permeability, connected via tight and adherens junctions. Cytosolic Ca²⁺ concentration is a major regulator of the BBB function. Using in vitro studies (calcium imaging, voltage imaging, nitric oxide measurement, immunocytochemistry, ECIS measurement) and in vivo approaches, we characterized the mechanisms of modulation of microvascular endothelial cells function and BBB permeability by G protein-estrogen receptor, Sigma-1R, thrombin, Platelet-Activating Factor, GPR55 agonists and omega 3 fatty acids. In collaboration with researchers from Temple University, we are currently examining the effect of SARS-CoV2 spike protein on the BBB permeability and the interaction with drugs of abuse.

Novel Ca²⁺ signaling mechanisms and Ca²⁺-mobilizing second messengers. Ca²⁺ is a fundamental and highly versatile, second messenger that modulates several cellular functions. Transient increases in cytosolic Ca²⁺ concentration are produced via Ca²⁺ influx across the plasma membrane and/or Ca²⁺ release from internal stores. Inositol trisphosphate (IP₃) and cyclic ADP ribose (cADPR), well known Ca²⁺-mobilizing second messengers, release Ca²⁺ from endoplasmic reticulum. Nicotinic acid adenine dinucleotide phosphate (NAADP) releases Ca²⁺ from endo-lysosomes. We characterized the second messenger role of NAADP in nucleus ambiguus neurons and vascular endothelium. Through collaborative work with researchers from Temple University and University College London, we contributed to the characterization of two-pore channels that mediate NAADP-evoked Ca²⁺ release from acidic organelles. Together with researchers from Temple University and University of Cambridge, we identified the role of choline as a second messenger. Choline, released subsequent to GPCR stimulation by various agonists, activates Sigma-1 receptors and potentiates IP₃-evoked Ca²⁺ signals. We are pursuing the characterization of this new signaling mechanism and its implications for physiology and pathophysiology in brain endothelial cells and neurons.

Signaling mechanisms in neurons involved in the autonomic control of cardiac function. The autonomic nervous system has a critical role in cardiovascular regulation. Autonomic imbalance, characterized by suppressed parasympathetic activity and/or increased sympathetic activity, has been implicated in the pathogenesis of several cardiovascular diseases. On the other hand, clinical and experimental studies indicate that reducing the heart rate through exercise training, pharmacological agents or vagal stimulation may improve the prognosis. Cardiac-projecting brainstem neurons of nucleus ambiguus play an essential role in the parasympathetic control of the heart rate. Using calcium and voltage imaging in dissociated, retrogradely-labeled, nucleus ambiguus neurons, we characterized the mechanism of action of several GPCR agonists (e.g., urocortin 3, nesfatin-1, urotensin II, PACAP, bradykinin). We complemented these studies with the ex-vivo examination of electrophysiological responses in brainstem slices and in vivo experiments in rats.

Blood-brain barrier permeability, Calcium signaling, Cannabinoid receptors, Cardiovascular regulation, GPCR signaling, Second messenger signaling.