Education

PHD, 1993, University of South Dakota School of Medicine
B.S., 1985, Kearney State College

Curriculum Vitae

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Relevant Publications

Bartlett, P. J., Antony, A. N., Agarwal, A., Hilly, M., Prince, V. L., Combettes, L., Hoek, J. B., and Gaspers, L. D. (2017) Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes. J Physiol 595, 3143-3164.

Wang, G., Memin, E., Murali, I., and Gaspers, L. D. (2016) The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes. Biochem J 473, 3903-3921.

Bartlett, P. J., Metzger, W., Gaspers, L. D., and Thomas, A. P. (2015) Differential Regulation of Multiple Steps in Inositol 1,4,5-Trisphosphate Signaling by Protein Kinase C Shapes Hormone-stimulated Ca2+ Oscillations. J Biol Chem 290, 18519-18533.

Gaspers, L. D., Bartlett, P. J., Politi, A., Burnett, P., Metzger, W., Johnston, J., Joseph, S. K., Hofer, T., and Thomas, A. P. (2014) Hormone-induced calcium oscillations depend on cross-coupling with inositol 1,4,5-trisphosphate oscillations. Cell reports 9, 1209-1218.

Bartlett, P. J., Gaspers, L. D., Pierobon, N., and Thomas, A. P. (2014) Calcium-dependent regulation of glucose homeostasis in the liver. Cell Calcium 55, 306-316.

Turner, J. D., Gaspers, L. D., Wang, G., and Thomas, A. P. (2010) Uncoupling protein-2 modulates myocardial excitation-contraction coupling. Circ Res 106, 730-738.

Gulati, P., Gaspers, L. D., Dann, S. G., Joaquin, M., Nobukuni, T., Natt, F., Kozma, S. C., Thomas, A. P., and Thomas, G. (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7, 456-465.

Smaili, S. S., Stellato, K. A., Burnett, P., Thomas, A. P., and Gaspers, L. D. (2001) Cyclosporin A Inhibits Inositol 1,4,5-Trisphosphate-dependent Ca2+ Signals by Enhancing Ca2+ Uptake into the Endoplasmic Reticulum and Mitochondria. J Biol Chem 276, 23329-23340.

Robb-Gaspers, L. D., and Thomas, A. P. (1995) Coordination of Ca2+ signaling by intercellular propagation of Ca2+ waves in the intact liver. J Biol Chem 270, 8102-8107.

Hajnoczky, G., Robb-Gaspers, L. D., Seitz, M. B., and Thomas, A. P. (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415-424.

Areas Of Interest

Our research focuses on the role of Ca2+ signaling in regulating mitochondrial physiology and pathophysiology and how adaptations in Ca2+ homeostasis may contribute to the onset and development of liver diseases.

Research in my laboratory focuses on Ca2+- dependent regulation of mitochondrial
physiology and hepatocyte metabolism (Fig. 1) and how adaptations in Ca2+ signaling may
contribute to the onset and development of liver diseases. We are currently studying
the effects of long-term alcohol intoxication on phosphoinositide-dependent Ca2+
signals with an emphasis on how alterations in Ca2+ signaling may lead to mitochondrial
dysfunction and tissue injury.
Chronic alcohol consumption can lead to a spectrum of alcoholic liver diseases
(ALD) including alcoholic fatty liver disease, alcoholic hepatitis, alcoholic cirrhosis
and in some cirrhotic patients hepatocellular carcinomas. Alcohol-induced tissue
injury starts predominately in hepatocytes located near the terminal hepatic veins
(pericentral zone) resulting in progressive alterations in liver morphology beginning
with fat infiltration, eventually leading to inflammation, apoptosis (i.e. Mallory
bodies), necrosis, and, finally fibrosis. Despite the overt toxicity of acute alcohol
exposure, only about 10-20% of human alcoholics develop end-stage liver disease at the
time of death. The factor(s) contributing to the progression between the early stages
of ALD, which are fully reversible, to more advanced stages of irreversible liver
injury are still poorly defined.
Our studies indicate that long-term alcohol feeding markedly potentiates Ca2+
responses elicited by phosphoinositide-specific phospholipase C (PI-PLC) linked
hormones resulting more sustained and prolonged increases in cytosolic Ca2+ levels.
Moreover, chronic alcohol feeding increased the protein levels of the voltage-sensitive
anion channel (VDAC) and mitochondrial Ca2+ uniporter (MCU); two key mitochondrial
proteins involved in Ca2+ transport across the outer and inner mitochondrial membranes.
The molecular changes in mitochondrial Ca2+ handling were associated with higher levels
of mitochondrial Ca2+ under basal conditions and more prolonged increases in matrix
Ca2+ after hormone stimulation. Importantly, we have shown that Ca2+-mobilizing
hormones selectively increase the formation of mitochondrial reactive
oxygen species (ROS) in hepatocytes from alcohol-fed animals, but not in controls.
Hormone-induced baseline-separated [Ca2+]i oscillations are an essential signaling
pathway to regulate many physiological functions of the liver including glucose
homeostasis, mitochondrial oxidative phosphorylation, stress responses and tissue
regeneration. However, alterations in cellular Ca2+ homeostasis leading to aberrant and
sustained rises in cytosolic Ca2+ have also been implicated in numerous diseases states
including non-alcoholic fatty liver disease. We are currently investigating the
hypothesis that alcohol-induced changes in receptor-coupled PLC? activity along with
the enhanced capacity to accumulate and retain Ca2+ in the mitochondrial matrix leads
to mitochondrial Ca2+ overload, increased ROS production, mitochondrial injury and
liver dysfunction. To test this idea, we plan to target specific proteins in the
receptor-coupled PLC signaling pathway to determine if attenuating hormone- dependent
Ca2+ increases can decrease alcohol-induced liver injury and slow the progression of
ALD.