Charles W. Leffler, Ph.D.


leffler image

UTHSC Distinguished Professor
Director, Laboratory for Research in Neonatal Physiology
Departments of Physiology and Pediatrics
Email: cleffler@uthsc.edu
Phone: 901-448-7122
Fax: 901-448-7126

Education

1969 B.S., University of Miami, Coral Gables, Florida
1971 M.S., University of Florida, Gainesville, Florida
1974 Ph.D., University of Florida, Gainesville, Florida

Full CV


Research Interest

Research in the laboratory concentrates on control of cerebral circulation. The primary focus of this research involves autocrine/paracrine control of the newborn cerebral microvasculature during physiologically stressful and pathological situations, and the cellular mechanisms involved in such control. We investigate autocrine and paracrine communication within the vessel wall, with specific current focus on the endogenous gasotransmitters, carbon monoxide and hydrogen sulfilde.

These images show the effect of the astrocyte toxin on confluent newborn astrocytes in primary culture. Immunostaining is for F-actin to show the cytoskeletal structure. Note the strong retractions of the astrocyte processes in the two panels treated with the astrocyte toxin as compared to the control panel on the left.

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Blood supply of the term newborn cerebral cortex viewed by intravital microscopy. In the brain the arteries and arterioles traverse the surface until the penetrating arterioles lead to the capillaries within the cortex. Capillary effluents are collected in venules that emerge from the gray matter back onto the surface.


Research Support

Hydrogen sulfide in newborn cerebral circulation

Principal Investigator: Charles W. Leffler, Ph.D.
Agency: National Heart, Lung, and Blood Institute
2 R01 HL042851  8/16/91-7/31/15

The research proposed is designed to address the hypothesis that H2S is a major component of microvascular control in the neonatal cerebral circulation.

Control of neonatal circulation

Principal Investigator: Charles W. Leffler, Ph.D.
Agency: National Heart, Lung, and Blood Institute
2 RO1 HL034059  4/1/85-3/31/17

The research proposed pursues the unifying hypothesis that, in newborn brain, asphyxia disrupts astrocyte CO signaling and cerebral arteriolar smooth muscle Ca2+ signaling and/or BKCa channel activity causing cerebrovascular dysfunction, while elevation of cytoprotective CO and bilirubin limit the dysfunction.

Cerebrovascular Stress and Circulating Endothelial Cells

Principal Investigator: Helena Parfenova, Ph.D., Co-investigator: Charles W. Leffler, Ph.D.
Agency: National Institute of Neurological Diseases and Stroke.
1 R01 NS063936 2/1/10-1/31/15

This project addresses the hypothesis that seizure-evoked cerebrovascular stress causes endothelial sloughing from cerebral vessels and appearance of brain-derived circulating endothelial cells in peripheral blood indicative of loss of endothelial vasodilator function in the neonatal cerebral circulation

Heme Oxygenase and Cerebral Vascular Injury

Principal Investigator: Helena Parfenova, Ph.D., Co-investigator: Charles W. Leffler, Ph.D.
Agency: National Heart, Lung, and Blood Institute
9 R01 HL099655 7/1/2004-6/30/2015

The research is designed to address the hypothesis that ROS are signaling molecules that increase the activity of HO-2 initiating a negative feedback antioxidant mechanism that promotes endothelial cell survival during neonatal seizure-induced cerebrovascular insult.

Selected Publications

Selected papers relevant to control of newborn cerebral circulation since 2009 (from 283).

  1. Kanu, A. and C.W. Leffler. Roles of glia limitans astrocytes and CO in ADP-induced pial arteriolar dilation in newborn pigs. Stroke 40: 930-935, 2009. PMCID:PMC2647584
  2. Basuroy, S., S. Bhattacharya, C. W. Leffler, and H. Parfenova. Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNFa in cerebral vascular endothelial cells. Am. J. Physiol. 296: C422-432, 2009 PMCID: PMC2660262
  3. Xi, Q. E. Umstot, G. Zhao, D. Narayanan, C.W. Leffler, and J. H. Jaggar. Glutamate regulates Ca2+ signals in smooth muscle cells of newborn piglet brain slice arterioles through astrocyte- and heme oxygenase-dependent mechanisms. Am. J. Physiol. 298: H562-H569, 2010 PMCID:PMC2822590
  4. Parfenova H., C.W. Leffler, D. Tcheranova, S. Basuroy, and A. Zimmermann. Epileptic seizures increase circulating endothelial cells in peripheral blood as early indicators of cerebral vascular damage. Am. J. Physiol. 298: H1687-H1698, 2010. PMCID:PMC2886638
  5. Knecht K.R., S. Milam, D. A. Wilkinson, A. L. Fedinec, and C.W. Leffler. Time Dependent Action of Carbon Monoxide on Newborn Cerebrovascular Circulation. Am. J. Physiol. 299: H70-H75, 2010 PMCID:PMC2904127
  6. Leffler C.W., H. Parfenova, S. Basuroy, J. H. Jaggar, E. S. Umstot, and A. L. Fedinec. Hydrogen sulfide and cerebral microvascular tone in newborn pigs. Am. J. Physiol. 300: H440-H447, 2011. PMCID:PMC3044062
  7. Basuroy S., D. Tcheranova, S. Bhattacharya, C.W. Leffler, and H. Parfenova. Nox4 NADPH oxidase–derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis. Am. J. Physiol. 300: C256-C265, 2011. PMCID:PMC3043629
  8. Liang G.H., Adebiyi A., Leo M.D., McNally E.M., Leffler C.W., Jaggar, J.H. Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels. Am. J. Physiol. 300: H2088-H2095, 2011 PMCID: PMC3119097
  9. Leffler C.W., H. Parfenova, J.H. Jaggar. Invited review: Carbon monoxide as an endogenous vascular modulator. Am. J. Physiol. 301 H1-H11, 2011. PMCID:PMC3129910
  10. Xi Q., D. Tcheranova, S. Basuroy, H. Parfenova, J. H. Jaggar, C.W. Leffler. Glutamate-induced calcium signals   stimulate CO production in piglet astrocytes. Am. J. Physiol. 301: H428-H433, 2011. PMCID: PMC3154668
  11. Kanu A. and C.W. Leffler. Arachidonic acid and prostaglandin E2-induced cerebral vasodilation is mediated by carbon monoxide independent of reactive oxygen species in piglets. .Am. J. Physiol. 301:H2482-7, 2011.PMCID:PMC323381
  12. Parfenova H., C.W, Leffler, S. Basuroy, J. Liu, A. L. Fedinec. Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures. Journal of Cerebral Blood Flow and Metabolism 32:1024-34, 2012 PMCID:PMC3367218
  13. Parfenova H., D. Tcheranova, S. Basuroy, A. L. Fedinec, J. Liu, and C.W. Leffler. Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate Am. J.Physiol. 302:H2257-H2066, 2012 PMCID:PMC3378289
  14. Liang G.H., Q Xi, C.W. Leffler CW, and Jonathan H. Jaggar. Hydrogen sulfide activates Ca2+ sparks to induce cerebral arteriole dilatation J Physiol 590: 2709-2720, 2012. PMCID:PMC3424726
  15. Parfenova H., C.W, Leffler, and S. Basuroy. CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am. J. Physiol.Cell 304: 1105-1115, 2013. PMCID:PMC3677176