James D. Lechleiter, Ph.D., Professor
University of Arizona
1984

Director, Core Optical Imaging Facility
(210) 567-6254
LECHLEITER@UTHSCSA.EDU

Dr. Lechleiter joined the department in March, 2000. He served as a member of the National Science Foundation (NSF) Study Panels on Instrumentation Development for Biomedical Research and served on Signal Transduction and Regulation. He has also served as an adhoc member for multiple National Institutes of Health (NIH) Special Emphasis Panels and study sections including: "Radiation Study Section", "Cell Development and Function-5", "Cell Biology and Physiology" and “Membrane Biology and Protein Processing”. Dr. Lechleiter has extensive experience with imaging technology, its application towards current problems in cell biology and is the director of the institutional Optical Imaging facility. He lectures in biophysics, cell biology and neurobiology as well as the fundamental principles of light microscopy. He also shares patents on a confocal microscope for simultaneous imaging with visible and ultraviolet light, a multi-photon laser scanning microscope using an acoustic optical detector and a provisional patent entitled “G-protein coupled receptor enhanced neuroprotection to treat brain injury” has been filed by the University of Texas Health Science Center at San Antonio on his behalf. Dr. Lechleiter is a member of both the Biophysical Society and the Society for Neuroscience.

Research Interests:
Our laboratory is interested in the molecular and cellular mechanisms of protection during ischemic stress, acute brain injury and aging. There are currently four distinct research projects.

First, we are investigating the impact of astrocyte mitochondrial metabolism on neuroprotection during aging. Our lab demonstrated that neuroprotection is diminished with age. We also discovered that astrocyte resistance to oxidative stress and neuroprotection could be enhanced by activation of a purinergic receptor (P2Y-R) signaling pathway in cultured astrocytes as well as in whole animal models. This enhanced protection pathway appears to be dependent on increased mitochondrial function in astrocytes.

The second research project in the laboratory is an investigation of the physiological function of the mitochondrial peptidyl prolyl isomerase, cyclophilin D (CyPD). Our lab discovered that overexpression of cyclophilin D (CyPD), a mitochondrial matrix protein, significantly increased the mitochondrial membrane potential (ΔΨ), oxygen (O₂) consumption and protected cells against apoptotic stimuli suggesting a critical role for CyPD in the regulation of cell survival. The goal of this project is to understand the mechanisms by which CyPD regulates mitochondria, understand its role in cell survival and ultimately, the aging process.

The third research project is an investigation of the mechanism (s) underlying the acute non-transcriptional stimulation of mitochondrial metabolism by thyroid hormone 3,5,3'-tri- iodothyronine (T₃) and shortened, mitochondrial targeted thyroid hormone receptors (TRs). Previous studies in our group showed evidence for a non-transcriptional regulation of Ca²⁺ signaling and mitochondrial metabolism by T₃-bound TRs. Our working hypothesis is that T₃ stimulation of TRs, increases mitochondria respiration either by directly regulation complex activity or by increasing substrate supply to the respiratory chain.

Finally, we are investigating the role of Ca²⁺ signaling during the initiation and recovery of cells from the unfolded protein response (UPR). Our data indicate that the ubiquitous Ca²⁺ dependent phosphatase, calcineurin (CN), plays a central role in the early phase of the UPR. In addition to investigating these processes in cell culture, we are determining the impact of CN activity on the UPR, in vivo, during brain ischemia.

Research Techniques:
Recombinant DNA, single and two-photon imaging techniques are used in our laboratory.
The model systems that we work with include cell culture, whole animal mice, C. elegans and Xenopus oocytes.

PUBLICATIONS:
Wu, J., Holstein, D., Upadhyay, G., Lin, D.T., Conway, S., Muller, E. and Lechleiter, J.D. (2007) Purinergic Receptor Stimulated IP₃-Mediated Ca²⁺ Release Enhances Neuroprotection by Increasing Astrocyte Mitochondrial Metabolism During Aging. J. Neuroscience 2007 Jun 13;27(24):6510-20.

Saelim, N., John, L.M., Park, J.S., Wu, J., Bai, Y., Camacho, P. and Lechleiter, J.D. (2004) Non-Transcriptional Modulation Of Intracellular Ca2+ Signaling By Ligand Stimulated Thyroid Hormone Receptor. J. Cell Biol. Dec 6; 167(5):915-24.

Lin, D. and Lechleiter, J.D. (2002) Mitochondrial Targeted Cyclophilin D Protects Cells From Cell Death by Peptidyl Prolyl Isomerization. J. Biol. Chem. 277, 31134-31141.

Jouaville, L.S., Ichas, F., Holmuhamedov, E., Camacho, P. and Lechleiter, J.D. (1995) Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature. Oct 5;377(6548):438-41 (with coverphoto).

Lechleiter, J.D., Girard, S., Peralta, E. and Clapham, D. (1991) Spiral calcium wave propagation and annihilation in Xenopus laevis oocytes. Science. Apr 5;252(5002):123-6 (with coverphoto).

Movie Title: Spiral Ca²⁺ waves in Xenopus oocyte.

Text Spiral Wave Movie
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. Studies in our laboratory revealed spiral waves of intracellular Ca²⁺ release induced by inositol 1,4,5 trisphosphate (IP₃) (Figure 2). 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.