Biomedical Summer Undergraduate Research Experience Program (B-SURE)
The University of Texas Health Science Center at San Antonio (UTHSCSA)

LECHLEITER, James D. (Cellular & Structural Biology):  Understanding the underlying mechanisms that govern Ca2+ release, uptake and sequestration is an important focus of our research. Intracellular Ca2+ is a ubiquitous second messenger that controls the activity of a multitude of enzymatic processes. Ca2+ cannot be metabolized in a manner that is analogous to the cycle of protein phosphorylation / de-phosphorylation. Rather, Ca2+ signals are mediated by changes in concentration of the ion.  Using single and two-photon microscopy, studies in our laboratory have revealed spiral waves of intracellular Ca2+ release induced by inositol 1,4,5 trisphosphate (IP3). Spiral waves are the trademark pattern formations of excitable media and have been described in other systems such as the classic Belousov-Zhabotinsky chemical reaction, aggregating slime mold, and electrical activity in neuronal tissue.  The active propagation of Ca2+ release in the form of Ca2+ waves provides an efficient mechanism to communicate hormonal signals over long distances.

        Recent work in our laboratory is focused mitochondrial physiology. Mitochondrial Ca2+ uptake and efflux regulate IP3-mediated Ca2+ release (4, 5), while accumulation of Ca2+ within mitochondria regulates both cell survival and cell death.  IP3R / mitochondrial Ca2+ signaling is at a key regulatory crossroad in cell development, maintenance and ultimately, cell death. Some of the going research projects in our laboratory are: 1) To investigate the mechanism (s) underlying the acute non-transcriptional stimulation of IP3-mediated Ca2+ signaling by thyroid hormone 3,5,3'-tri-iodothyronine (T3) and the thyroid hormone bA1 receptor (TRbA1).  2) To investigate the underlying mechanism (s) of regulation of the opening of the mitochondrial permeability transition pore (mPTP) by Cyclophilin D (CyPD) and to examine the modulation of this process by IP3-mediated Ca2+ release. 3) To examine how manipulation of CyPD protein levels affects resistance to oxidative stress and lifespan in two whole-animal model systems, C. elegans and mice. 4) To identify and clone loss-of-function genes controlling mitochondrial Ca2+ uptake and efflux. 5) To determine the underlying mechanism (s) of decreased IP3R / Mitochondrial Ca2+ signaling in Astrocytes during aging. 6) To investigate the role of oxidative stress on the age-dependent changes IP3R / Mitochondrial Ca2+ signaling in astrocytes. 7) To determine the impact of impaired IP3R / Mitochondrial Ca2+ signaling in astrocytes on neuroprotection. The significance of these studies is three-fold. First, control of intracellular Ca2+ is central to many cell signaling pathways including cell growth, differentiation and death. Second, mitochondria are known to play key regulatory roles in neuronal excitotoxicity and apoptosis. And finally, dysfunctional mitochondria, which accumulate with age and/or oxidative stress are promising targets for therapeutic intervention.

James D. Lechleiter's Web Page.