USA Department of Physiology & Cell Biology Faculty

Academic Faculty

▼   Troy Stevens, Ph.D.

Troy Stevens, Ph.D. Troy Stevens, Ph.D.

Lenoir Louise Locke Chair of Physiology and Cell Biology
Professor

Ph.D.: Colorado State University
Post-doctoral: University of Colorado

(251) 460-6056
tstevens@southalabama.edu 

Research Interests

The Stevens lab studies the endothelium, with a particular interest in endothelial cell heterogeneity.  Considerable work in the past 10 years has demonstrated that pulmonary artery, capillary and vein endothelial cells are highly specialized in order to perform the physiological functions that are relevant to their vascular location.  The mechanisms responsible for establishing such heterogeneity are still poorly understood, and are the focus of our ongoing work.

Endothelium forms a semi-permeable barrier that separates blood from underlying tissue.  Strength of this barrier, and the nature of cell-cell adhesion, changes dramatically from the pulmonary artery to the capillaries, where capillary endothelial cells form an especially tight barrier.  During the course of inflammation, endothelial cells transiently decrease cell-cell adhesion and form intercellular gaps.  Calcium entry through ion channels on the plasma membrane is an important signal that triggers cytoskeletal reorganization and promotes gap formation.

Our group has worked to identify calcium channels that provide the calcium source responsible for inter-endothelial cell gap formation.  We have found that proteins belonging to the canonical transient receptor potential family of proteins (TRPC) contribute subunits to this channel.  More specifically, TRPC1, TRPC3 and TRPC4 appear to interact to form the channel pore.  TRPC4, in particular, is linked directly to the cytoskeleton.  TRPC4 binds to protein 4.1, which tethers the channel to the spectrin membrane skeleton and the cortical actin rim.  Ongoing studies suggest that this linkage establishes a privileged niche, where calcium entering through the channel serves as a catalyst to reorganize peripheral actin and enable intercellular gap formation.  It will be important to continue resolving the molecular anatomy of this channel, to better understand how it is activated, and how calcium permeation through the channel impacts endothelial shape during the cell's response to inflammation.

While calcium entry through a TRPC channel disrupts the endothelial cell barrier, the second messenger adenosine 3'5'-cyclic monophosphate (cAMP) strengthens the barrier.  cAMP activates two downstream signals, including protein kinase A and exchange protein activated by cAMP (EPAC), which collectively strengthen the cortical actin rim and support junctional complexes.  Hormones such as epinephrine increase endothelial cAMP, and therefore have anti-inflammatory actions. 

In contrast to the anti-inflammatory actions of epinephrine, pathogenic bacteria, such as Pseudomonas aeruginosa, have evolved mechanisms to utilize adenylyl cyclase toxins to generate cAMP and disrupt the endothelial cell barrier.  P. aeruginosa utilizes a type III secretion system to inject exotoxin Y (exoY) into host cells, including the endothelium.  Once in the host cell, exoY binds a mammalian cofactor and becomes an active enzyme, generating cAMP.  Unlike the cAMP that is synthesized by the host cell, which is primarily produced at the plasma membrane, exoY generates cAMP in the cytosol.  This cytosolic cAMP does not strengthen the cortical actin rim, but rather, disassembles microtubules leading to intercellular gap formation.  Hence, studies on the function of exoY have revealed previously unappreciated mechanisms of cAMP signal transduction, cytoskeletal regulation of endothelial cell barrier, and mechanisms of bacterial pathogenesis.  It will be important to continue these studies, to better understand how exoY becomes localized to target microtubule structures, and how the toxin serves to impact bacterial dissemination and pathogenicity.

Representative Publications

  1. Wu S, Moore TM, Brough G, Li M, and Stevens T. Cyclic nucleotide gated channels mediate membrane depolarization following activation of store operated Ca2+ entry in endothelial cells.  J. Biol. Chem., 275:  18887-18896, 2000.
  2. Stevens T, Garcia JGN, Shasby DM, Bhattacharya J, and Malik AB.  Mechanisms regulating endothelial cell barrier function.  Am. J. Physiol., 279:  L419-L422, 2000.
  3. Moore T, Norwood N, Creighton J, Babal P, Brough G, Shasby D, and Stevens T.  Receptor-dependent activation of store-operated Ca2+ entry increases endothelial cell permeability.  Am. J. Physiol., 279:  L691-L699, 2000.
  4. Norwood N, Moore TM, Dean D, Bhattacharjee R, Creighton J, Babal P, and Stevens T.  Store operated Ca2+ and endothelial cell permeability.  Am. J. Physiol., 279:  L815-L824, 2000.
  5. Stevens T.  Pulmonary vasoconstriction induced by Gq agonists.  Is there a role for store operated calcium entry?  Am. J. Physiol., 280:  L866-L869, 2001.
  6. Brough G, Wu S, Moore TM, Li M, Dean N, and Stevens T.  Contribution of endogenously expressed Trp-1 to a Ca2+ selective store operated Ca2+ entry pathway.  FASEB J., 15:  1727-1738, 2001.
  7. Wu S, Sangerman J, Li M, Brough G, Goodman S, and Stevens T.  Essential control of an endothelial cell ISOC by the spectrin membrane skeleton.  J. Cell Biol., 154:  1225-1233, 2001.
  8. Stevens T, Rosenberg B, Aird W, Quertermous T, Garcia JGN, Hebbel R, Tuder R, Garfinkel S.  NHLBI workshop report:  Endothelial cell phenotypes in heart, lung and blood diseases.  Am. J. Physiol., 281:  C1422-C1433, 2001.
  9. Parker J, Stevens T, Randall J, Sybert C, Yoshikawa S, and Penton A.  Hydraulic conductance of segmental endothelial phenotypes in pulmonary circulation.  Proc. 7th World Cong. Microcirc., pp. 505-511, 2002.
  10. Cioffi D, Moore TM, Schaack J, Creighton J, Cooper DMF and Stevens T.  Dominant regulation of inter-endothelial cell gap formation by the calcium-inhibited type 6 adenylyl cyclase.  J. Cell Biol., 157:  1267-1278, 2002.
  11. Stevens T.  Bronchial endothelial cell phenotypes and the form:function relationship.  Am. J. Physiol.  283:  L518-L519, 2002.
  12. Wang Q, Pfeiffer GR, Stevens T, and Doerschuk CM.  Pulmonary microvascular and arterial endothelial cells differ in their responses to ICAM-1 ligation.  Am. Rev. Resp. Crit. Care Med.,  166:  872-877, 2002.
  13. Norwood N and Stevens T.  Molecular motors in control of store operated Ca2+ entry.  Cell Biochem. Biophys.,  37:  53-70, 2002.
  14. Creighton J, Masada N, Cooper DMF, and Stevens T.  Coordinate regulation of membrane cAMP by calcium inhibited adenylyl cyclase (type 6) and phosphodiesterase (type 4) activities.  Am. J. Physiol., 284:  L100-L107, 2003.
  15. Cioffi DL, Wu S, and Stevens T.  On the endothelial cell ISOC.  Cell Calcium. 33:  323-336, 2003.
  16. Wu S, Haynes J, Taylor J, Brough GH, Li M, and Stevens T.  Cav3.1 (α1G) T-type Ca2+ channels mediate vaso-occlusion of sickled erythrocytes in lung microcirculation.  Circ. Res., 93:  346-353, 2003.
  17. Chatterjee S, Al-Mehdi A, Levitan I, Stevens T, and Fisher AB.  Shear stress increases expression of a KATP channel in rat pulmonary microvascular endothelial cells.  Am. J. Physiol., 285:  C959-967, 2003.
  18. King J, Hamil T, Creighton J, Wu S, Bhat P, McDonald F, and Stevens T.  Structural and functional characteristics of lung macro- and microvascular endothelial cell phenotypes.  Microvasc. Res., 67:  139-151, 2004.
  19. Li J, Zheng M, Tang ZL, Stevens T, Pitt B, and Li S.  CpG DNA-mediated immune response in pulmonary endothelial cells.  Am. J. Physiol., 286:  L808-L816, 2004.
  20. Gebb SA and Stevens T. On lung endothelial cell heterogeneity. Microvasc. Res., 68:  1-12, 2004.
  21. King JA, Ofori-Acquah SF, Stevens T, Al-Mehdi A., Fodstad O. and Jiang WG.  Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator.  Breast Canc. Res., 6:  478-487, 2004.
  22. Ihida-Stansbury K, Gebb SA, McKean DM, Martin JF, Stevens T, Kaplan-Alburquerque N, and Jones PL.  The paired-related homeobox gene transcription factor Prx1 is required for lung vascularization and normal alveolar development.  Circ. Res., 94:  1507-1514, 2004.
  23. Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JGN, Kao PN, Knowles JA, Loyd JE, McGoon MD, Morse JH, Nichols WC, Rabinovitch M, Rodman DM, Stevens T, Tuder RM, Voelkel NF, and Gail DB. Pulmonary arterial hypertension: future directions. Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop. Circulation, 109:  2947-2952, 2004.
  24. Sayner SL, Frank DW, King J, Chen H, VandeWaa J, and Stevens T.  Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by P. aeruginosa ExoY.  Circ. Res., 95:  196-203, 2004.
  25. Metze B, Ofori-Acquah S, Stevens T, and Balczon R.  Stat3 activity is required for centrosome duplication in Chinese hamster ovary cells. J. Biol. Chem., 279:41801-41806, 2004.
  26. Sayner S and Stevens T.  Adenylyl cyclase and cAMP regulation of the endothelial barrier.  In:  Perspectives on Lung Endothelial Barrier Function.  Editor:  C. E. Patterson. Elsevier Science, ISBN: 0-444-51834-7, pg. 139-164, 2005.
  27. Thorin E, Stevens T, and Patterson CE.  Heterogeneity of Lung Endothelial Cells.  In:  Perspectives on Lung Endothelial Barrier Function.  Editor: C. E. Patterson. Elsevier Science, ISBN: 0-444-51834-7, pg. 277-310, 2005.
  28. Wu S, Cioffi E, Alvarez D, Sayner SL, Chen H, Cioffi DL, King J, Creighton JR, Townsley M, Goodman SR, and Stevens T.  Essential role of a Ca2+ selective store operated current (ISOC) in endothelial cell permeability: determinants of the vascular leak site.  Circ. Res., 96(8):856-863, 2005.
  29. Stevens T.  Calcium inhibited adenylyl cyclase (AC6) controls endothelial cell barrier function.  In: Proinflammatory Signaling Mechanisms in the Pulmonary Circulation.  Editor: J. Bhattacharya. Humana Press, pg. 203-215, 2005.
  30. Wu S, Cioffi D, and Stevens T.  Receptor-operated Ca2+ channels.  In: Ion Channels in the Pulmonary Vasculature.  Editor: J. X. Yuan. Taylor and Francis, Boca Raton, Florida pg. 99-124, 2005.
  31. Cioffi D, Wu S, and Stevens T.  Transient receptor potential cation channels and store-operated Ca2+ channels. In: Ion Channels in the Pulmonary Vasculature.  Editor: J. X. Yuan. Taylor and Francis, Boca Raton, Florida, pg. 125-146, 2005.
  32. Al-Mehdi A, Schaphorst KL and Stevens T.  Lung endothelial heterogeneity. In: Encyclopedia of the Microvasculature.  Editor: J.G.N. Garcia.  Elsevier Science, pg. 465-470, 2005.
  33. Cioffi DL, Wu S, Alexeyev M, Goodman SR, Zhu MX, and Stevens T.  Activation of the Endothelial Store-Operated ISOC Ca2+ Channel Requires Interaction of Protein 4.1 With TRPC4.  Circ. Res., 97:1164-1172, 2005.
  34. Stevens T.  Molecular and cellular determinants of lung endothelial cell heterogeneity. Chest, 128: 558S - 564S, 2005.
  35. Stevens T, Kasper M, Cool C, and Voelkel NF.  Pulmonary circulation and pulmonary hypertension. In: Endothelial Cells in Health and Disease.  Editor:  W. C. Aird.  Informa Healthcare, pages 417-438, 2005.
  36. Zhu B, Strada S, Stevens T.  Cyclic GMP-specific phosphodiesterase 5 regulates cell growth and apoptosis in pulmonary endothelial cells.  Am. J. Physiol., 289:L196-206, 2005.
  37. Matthay MA, Christman JW, Pitt BR, Schwiebert LM, Stevens T, and Ware LB.  Perspectives, translational research, and letters to the editor.  Am. J. Physiol., 290:L621, 2006. [Editorial]
  38. He F, Li J, Mu Y, Kuruba R, Ma Z, Wilson A, Alber D, Jian Y, Stevens T, Watkins S, Pitt B, Xie W, and Li S.  Downregulation of endothelin-1 farnesoid X receptor in vascular endothelial cells.  Circ. Res., 98:192-199, 2006.
  39. Sayner S, Alexeyev M, Dessauer CW, and Stevens T.  Soluble adenylyl cyclase reveals the significance of cAMP compartmentation on pulmonary microvascular endothelial cell barrier.  Circ. Res., 98:675-681, 2006.
  40. Masedunskas A, King JA, Tan F, Cochran R, Stevens T, Sviridov D and Ofori-Acquah SF. Activated leukocyte cell adhesion molecule is a component of the endothelial junction involved in transendothelial monocyte migration.  FEBS Lett., 580:2637-45, 2006.
  41. Sayner S and Stevens T.  Soluble adenylate cyclase reveals the significance of compartmentalized cAMP on endothelial cell barrier function. Biochemical Society Transactions, 34:492-494, 2006.
  42. Parker J, Stevens T, Randall J, Weber D, and King J.  Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers. Am. J. Physiol., 291:L30-7, 2006.
  43. Cioffi D and Stevens T.  Regulation of endothelial cell barrier function by store operated calcium entry.   Microcirculation, 13:709-723, 2006.
  44. Zhang L, Croix C, Cao R, Wasserloos K, Watkins SC, Stevens T, Li S, Tyurin V, Kagan VE and Pitt BR. Cell-surface protein disulfide isomerase is required for transnitrosation of metallothionein by S-nitroso-albumin in intact rat pulmonary vascular endothelial cells.  Exp. Biol. Med. 231:1507-15, 2006.
  45. Stevens T.  Microheterogeneity of lung endothelium. In:  Endothelial Biomedicine. Editor: William C. Aird, Cambridge University Press, pages 1161-1170, 2007.
  46. Lowe K, Alvarez D, King J, and Stevens T. Phenotypic heterogeneity in lung capillary and extra - alveolar endothelial cells. Increased extra-alveolar endothelial permeability is sufficient to decrease compliance. J. Surg. Res. 143:170-177, 2007.
  47. Creighton J, Zhu B, Alexeyev M, and Stevens T. Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation. J. Cell Sci. 121:110-119, 2007.
  48. Stevens T, Gillespie MN. The hyperproliferative endothelial cell phenotype in idiopathic pulmonary arterial hypertension. Am. J. Physiol., 293:L546-547, 2007.
  49. Wu S, Chen H, Alexeyev MF, King JAC, Moore TM, Stevens T, and Balczon RD. Microtubule motors regulate ISOC activation necessary to increase endothelial cell permeability. J. Biol. Chem., 282:34801-34808, 2007.
  50. Clark J, Alvarez D, Alexeyev M, King J, Huang L, Yoder M, and Stevens T. Regulatory role for nucleosome assembly protein-1 in the proliferative and vasculogenic phenotype of pulmonary endothelium. Am. J. Physiol., 294:L431-L439, 2008.
  51. Alvarez D, Huang L, King J, Yoder M, and Stevens T. Lung microvascular endothelium is enriched with progenitor cells that exhibit rapid vasculogenic capacity. Am. J. Physiol., 294:L419-L430, 2008.
  52. Stevens T.  Epithelium:  sticking it out, together.  Am. J. Physiol., 294:L440-L441, 2008.
  53. Haynes Jr J, Obiako B, Hester RB, Baliga BS, Stevens T. Hydroxyurea attenuates activated neutrophil-mediated sickle erythrocyte membrane phosphatidylserine exposure and adhesion to pulmonary vascular endothelium.  Am J. Physiol., 294:H379-H385, 2008.
  54. Ofori-Acquah SF, King J, Voelkel N, Schaphorst KL, and Stevens T.  Heterogeneity of barrier function in the lung reflects diversity in endothelial cell junctions. Microvas. Res., 75:391-402, 2008.
  55. King J, Agarwal S, Syklawer E, Prasain N, Chen H, Resmondo J, McDonald F, Bauer N, Alvarez D, Wu S, Stevens T, Shevde L, Moore T, and Townsley M.  Quantum Dots -  Utilization in TEM. Microsc. Microanal., 14(Suppl2): 702-703, 2008.
  56. Franks TJ, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Englehardt J, Frid M, Herzog E, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, et al. NHLBI Workshop Summaries on Resident Cellular Components of the Human Lung. Proc. Am. Thorac. Soc., 5:763-766, 2008.
  57. Stevens T, Phan S, Frid MG, Alvarez D, Herzog E, and Stenmark KR.  NIH workshop on Lung Vascular Cell Heterogeneity:  endothelium, smooth muscle and fibroblasts.  Proc. Am. Thorac. Soc., 5:783-791, 2008.
  58. Rai PR, Cool CD, King JAC, Stevens T. Burns N, Winn RA, Kasper M, and Voelkel NF.  The cancer paradigm of severe angioproliferative pulmonary hypertension (SAPPH).  AM. J. Resp. Crit. Care Med., 178:558-564, 2008.
  59. Zhu B, Zhang L, Alexeyev M, Alvarez DF, Strada SJ, and Stevens T.  Type 5 phosphodiesterase expression is a critical determinant of the endothelial cell angiogenic phenotype.  Am. J. Physiol., 296:  L220-228, 2009.
  60. Prasain N and Stevens T.  The actin cytoskeleton in endothelial phenotypes.  Microvasc. Res., 77:  53-63, 2009.
  61. Prasain N, Alexeyev M, and Stevens T.  Soluble adenylyl cyclase-dependent microtubule disassembly reveals a novel mechanism of endothelial cell retraction.  Am. J. Physiol., 297:  L73-L83, 2009.
  62. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, and Haworth SG.      Development and pathology of pulmonary hypertension.  J. Am. Coll. Cardiol.,  54:  S3-S9, 2009.
  63. Cioffi D, Lowe K, Alvarez DF, Barry C, and Stevens T.  TRPing on the lung endothelium.  Antiox. Redox. Signal., In Press.
  64. Cioffi D, Barry C, and Stevens T.  Studies on the structure and function of the calcium selective store operated calcium entry current.  In:  Membrane Receptors, Channels and Transporters in the Pulmonary Circulation.  Editors:  Jeremy P.T. Ward and Jason X.-J. Yuan, Humana Press, In Press.
▼   Mikhail Alexeyev, Ph.D. 

Mikhail Alexeyev, Ph.D. 

Associate Professor

Postdoctoral Studies: Texas Heart Institute
Ph.D.: National Academy of Sciences of Ukraine, Kiev

Recent Publications

Research Interests

Mitochondrial DNA Maintenance, Damage, Repair, Degradation and Mutagenesis. Mitochondria as Targets for Gene Therapy.

Mitochondria are central players in processes of cell life and death. Mitochondrial dysfunction has been linked to such diverse conditions as mitochondrial diseases, cardiovascular disease, cancer, diabetes, and aging. Research in this lab is directed towards understanding the mechanisms for the maintenance of mtDNA integrity, developing mouse models for mitochondrial diseases caused by mutations in mtDNA as well as devising gene therapy strategies for mitochondrial disorders.

Representative Publications

  • Shokolenko, I.N., M.F. Alexeyev, S.P. LeDoux, and G.L. Wilson, The approaches for manipulating mitochondrial proteome. Environ Mol Mutagen, 2010. 51(5): p. 451-61.
  • Alexeyev MF. Is there more to aging than mitochondrial DNA and reactive oxygen species? FEBS J. 2009 Oct;276(20):5768-87.
  • Shokolenko I, Venediktova N, Bochkareva A, Wilson GL, Alexeyev MF. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res.  2009 37: 2539-2548 
  • Pastukh V, Shokolenko IN, Wilson GL, Alexeyev MF. Mutations in the passenger polypeptide can affect its partitioning between mitochondria and cytoplasm : Mutations can impair the mitochondrial import of DsRed. Mol Biol Rep. 2008 Jun;35(2):215-23.
  • Alexeyev MF, Venediktova N, Pastukh V, Shokolenko I, Bonilla G, Wilson GL. Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther. 2008 Apr;15(7):516-23.
  • Pastukh V, Shokolenko I, Wang B, Wilson G, Alexeyev M. Human mitochondrial transcription factor A possesses multiple subcellular targeting signals. FEBS J. 2007 Dec;274(24):6488-99.
  • Alexeyev MF, Ledoux SP, Wilson GL Mitochondrial DNA and aging. In.P. Michael Conn ed. Handbook of models for human aging. Elsevier, 2006
  • Ruchko M, Gorodnya O, Ledoux SP, Alexeyev MF, Al-Mehdi AB, Gillespie MN. Mitochondrial DNA damage triggers mitochondrial dysfunction and apoptosis in oxidant-challenged lung endothelial cells. Am J Physiol Lung Cell Mol Physiol.288:L530-5 (2005).
  • Shokolenko IN, Alexeyev MF, LeDoux SP, Wilson GL. TAT-mediated protein transduction and targeted delivery of fusion proteins into mitochondria of breast cancer cells. DNA Repair (Amst). 4:511-8 (2005).
  • Alexeyev MF, LeDoux SP, Wilson GL Mitochondrial DNA and aging Clin Sci (Lond). 107:355-64 (2004)
  • Rachek L, Grishko V, Alexeyev M, Pastukh V, LeDoux S, Wilson GL Endonuclease III and endonuclease VIII conditionally targeted into mitochondria enhance mitochondrial DNA repair and cell survival following oxidative stress Nucleic Acids Res.32:3240-7 (2004).
  • Shokolenko IN, Alexeyev MF, Robertson FM, LeDoux SP, Wilson GL. The expression of exonuclease III from E. coli in mitochondria of breast cancer cells diminishes mitochondrial DNA repair capacity and cell survival after oxidative stress. DNA Repair (Amst) 2:471-82 (2003).
▼   Stephen T. Ballard Ph.D. 

Stephen T. Ballard Ph.D. Stephen T. Ballard Ph.D. 

Professor

B.S.: North Carolina State University
M.S.: University of Kentucky
Ph.D.: University of North Carolina

sballard@southalabama.edu

Recent Publications

Research Interests

Control of the volume of surface liquid which covers the pulmonary epithelium is critical for normal mucociliary clearance and for efficient gas exchange. The role that active transepithelial ion transport plays as a driving force for liquid movement across the pulmonary airways is currently under study. We measure the bioelectric properties of isolated bronchi and bronchioles as correlates of active ion transport activity. We then use selective transport inhibitors and stimulators to determine which transport pathways are present and how these processes are regulated. In persons afflicted with cystic fibrosis (CF), a molecular defect in an epithelial chloride channel is present that leads to a myriad of pathological problems, the most critical of which involves secretion of thickened, dehydrated mucus into the airways. A major focus of our research is to determine how such defects in chloride ion transport are mechanistically related to the development of the symptoms observed in cystic fibrosis patients. Our findings suggest that fluid secretion from the submucosal glands of the trachea and bronchial airways is disrupted in CF, leading to the production of a highly concentrated mucus that is poorly cleared from the airways by cough or by mucociliary transport. We use techniques for measuring liquid secretion, mucociliary transport, and ciliary beat frequency to determine the importance of interactions between periciliary fluid, mucus, and cilia at the airway surface for maintaining normal ciliary clearance. We also model important aspects of CF lung disease in porcine isolated lungs by perfusing the vasculature with selective inhibitors of anion secretion. We are now expanding our studies by exploring new ways to model CF lung disease including use of in vitro (siRNA) and in vivo (screening non-human animal populations for mutant CFTR) approaches. We believe that our findings are of great importance for understanding the underlying cause of CF lung disease and for development of effective treatments.

▼   Michael V. Cohen, M.D. 

Michael V. Cohen, M.D. Michael V. Cohen, M.D. 

Professor

M.D.: Harvard Medical School
Cardiology Fellowship: Peter Bent Brigham Hospital, Boston, MA

Phone: 251-460-6812
Fax: 251-460-6464
mcohen@southalabama.edu

Recent Publications

Research Interests

When a coronary artery is obstructed by either cholesterol plaque or thrombus, the region served by that artery loses its blood supply and, therefore, its supply of oxygen and metabolite. Heart muscle cells begin to die within 15 or 20 minutes. To restore coronary flow in these patients thrombolytic drugs can be given to dissolve the blood clot or catheter-based techniques can be used to remove or compress the plaque and reestablish luminal patency. Unfortunately there is always some delay in restoration of flow, and there is always unavoidable death of heart muscle. Because heart muscle cells cannot be regenerated, the loss of contractile mass leaves the patient with a permanently weakened heart which often leads to heart failure, a major cause of morbidity and death in these patients. The goal of my research is discovery of an intervention which will delay the rate of cell death in such a patient so that more muscle would survive the heart attack.

In 1986, it was shown that heart cells could be made very resistant to death following loss of blood flow if they were first exposed to a brief period of blood flow deprivation followed by reperfusion. Within minutes of this cycle of ischemia/reperfusion the heart actually adapted itself to much better tolerate a subsequent, more prolonged cessation of blood flow. If understood, this process, called preconditioning, should provide a key to designing a therapy which could spare ischemic myocardium. My colleague James M. Downey and I have studied the signaling involved in preconditioning and have identified many of the critical steps including binding of Gi-coupled adenosine, bradykinin, and opioid receptors, downstream activation of Akt, ERK, and nitric oxide synthase, opening of KATP channels and release of reactive oxygen species, and activation of PKC which somehow sensitizes adenosine A2B receptors allowing successful ligand binding. This in turn leads to phosphorylation of other kinases including ERK, Akt, nitric oxide synthase, and GSK-3β with the ultimate goal of closing mitochondrial permeability transition pores, the putative end-effectors. However, the intellectual satisfaction at uncovering this signaling is challenged by the poor likelihood that there would ever be a derived intervention that could be clinically useful since this preconditioning must be initiated before ischemia, whereas patients present with myocardial infarction following coronary occlusion and onset of ischemia.

But then it became apparent that brief coronary occlusions immediately after a cycle of ischemia/reperfusion were just as effective as preconditioning in which the brief occlusions occurred before the long coronary occlusion. Thus postconditioning could effectively decrease infarction. And this phenomenon could be replicated with certain pharmacologic agents administered just before reperfusion. One family of agents we have extensively studied is platelet anti-aggregatory P2Y12 receptor antagonists such as cangrelor and ticagrelor. And now virtually all patients with acute myocardial infarction receive these agents before catheter-based interventions to remove thrombus and restore perfusion. Hence all of these patients are indeed postconditioned and “protected”. Despite use of these cardioprotective drugs, infarction is not eliminated. We are now identifying interventions which can be used to augment protection induced by P2Y12 agents. Although hypothermia and cariporide can each augment cardioprotection, neither can easily be used clinically. But a caspase-1 antagonist which blunts inflammation and pyroptosis has proven to be quite promising. Future research will seek to establish the mechanism and properties to permit extrapolation to clinical use.

▼   James M. Downey Ph.D. 

James M. Downey Ph.D. James M. Downey Ph.D. 

Professor Emeritus

Ph.D.: University of Illinois
Postdoctoral Studies: Harvard Medical School

Phone: 251-460-6818
Fax: 251-460-6386
jdowney@southalabama.edu

Publications | Full CV [PDF]

Research Interests

A heart attack occurs when a blood clot forms in a coronary artery depriving blood flow from a region of the heart, a condition termed ischemia. Current therapy is to reopen the artery but blood flow is seldom restored before a significant amount of the heart muscle has died. Because lost heart muscle cannot be regenerated the patient is left with a weakened heart and heart failure often occurs. Our research is directed toward identifying therapies that prevent cell death in ischemic heart. We have found that population of Gi-coupled receptors prior to ischemia makes the heart very resistant to cell death. Our current research is directed at mapping the complex signal transduction pathway involved. To date we have found that population of surface receptors with bradykinin or opioids, through their G-proteins, cause transactivation of epidermal growth factor receptors. That in turn activates PI3 kinase which causes activation of Akt through phosphorylation. Akt activation results ultimately in opening of mitochondrial ATP sensitive potassium channels, mKATP. As potassium enters the mitochondria it causes them to release free radicals which act as a signal to activate protective kinases such as PKC.

Our current interest is in the pathways that are active when the preconditioned heart is reperfused after the ischemic insult. PKC sensitizes the heart to adenosine at the A2b receptor. That allows endogenous adenosine to activate signaling from this normally low affinity receptor. The A2b receptor controls the survival kinases ERK and Akt in the heart. Those kinases are thought to act through GSK3B to inhibit the mitochondrial permeability transition pore formation that destroys many of the heart's mitochondria in the first minutes of reperfusion. Many drugs and interventions that can activate the conditioning pathway have been identified.

We study these pathways using whole hearts where we measure tissue death after a standardized ischemic insult as an end-point. We can then use pharmacologic tools to both trigger and block the protection at specific points in the pathway. Secondly, we study heart samples from hearts receiving various treatments and measure the chemical signals directly using protein chemistry. Finally, we study isolated heart muscle cells where the free radical burst involved in signaling can be measured with radical-sensitive dyes and again use activators and blockers to determine the steps between the receptor activation and the free radical burst.  We found that platelet inhibitors belonging to the P2Y12 inhibitor family put the heart into a preconditioned state if they are present in the blood at the time of reperfusion.  Since most of today's patients treated for acute myocardial infarction receive a loading dose of a P2Y12 blocker prior to reperfusion therapy they are already in a preconditioned state.  That would explain why powerful preconditioning mimetics have performed poorly in recent clinical trials. What is needed is a drug that protects by a different mechanism than the conditioning pathway.

Most recently I have become interested in the role of mitochondrial DNA as a promoter of cell death during acute myocardial infarction. I proposed that fragmented mitochondrial DNA released from irreversibly injured mitochondria acts as a DAMP (damage associated molecular pattern) and triggers a local inflammatory reaction in adjacent cells which kills them causing them to release their mitoDNA. This causes a spreading wave of necrosis across the ischemic zone. IV injection of mitochondrially-directed DNA repair enzymes or of DNase prevents this domino effect and greatly limits infarct size. The executioner of the inflammation appears to be caspase-1 as we find caspase-1 inhibitors to be highly protective. Because these drugs protect by a different mechanism than conditioning they can further limit infarct size in animals already protected with a platelet inhibitor.

Teaching Interests

I have been teaching cardiovascular physiology to the freshman medical students since 1972, first at the University of South Florida and then at my present location at the University of South Alabama.  I developed a number of interactive teaching laboratories to complement my lectures. Originally those laboratories involved live animals but today they either use student volunteers (ECG lab) or computer simulations including the USA cardiovascular simulator which is a free downloadable teaching program that the student can use to illustrate the complex the interaction between the heart, whose output is determined by its preload and afterload, and the peripheral vasculature that actually determines preload and afterload. In 1992 I contributed 8 cardiovascular chapters to Johnson’s Essential Medical Physiology (Raven).  This was a text book designed for medical students and was adopted by a number of medical schools as an assigned text. It was revised in 1998 and again in 2003 (Elsevier). I still lecture in our cardiovascular modules for the medical students and for the graduate students.

▼   Mike T. Lin, Ph.D.

Mike T. Lin, Ph.D.Mike T. Lin, Ph.D.

Associate Professor

B.S.: Biochemistry, University of British Columbia
Ph.D.: Physiology, Loma Linda University
Postdoc: Oregon Health and Science University

mlin@southalabama.edu

Publications

Research Interests

My laboratory currently focuses on trafficking of calcium-activated potassium channels (eg. BK, IK, and SK channels) in two main areas: neuroscience and vascular biology.

Neuroscience: Long-term synaptic plasticity (LTP) is widely thought to be the cellular substrate for learning and memory, thus mechanisms by which this plasticity is induced and maintained are potential therapeutic targets for the wide range of disorders that affect these processes. My recent work has found an unexpected role for SK2 channels in the expression of long-term plasticity, and my new findings suggest a novel mechanism for dual regulation of SK2 channel and glutamate receptor levels within dendritic spines that is orchestrated by previously unappreciated synaptic proteins.

Vascular biology: Post-menopause, aging, and hypertension are all major risk factors for cardiovascular disease morbidity and mortality: the leading cause of death in the United States. Hypertension, the so-called ‘silent killer’, usually does not present clinical symptoms until complications emerge. Physiological changes including menopause and aging induce irreversible changes in the cardiovascular system that frequently result in diminished endothelium-dependent regulation of vascular tone and can lead to hypertension. Ca2+ signaling in vascular endothelium is a key regulator for many of the endothelium-derived vasoactive factors, including endothelins, prostaglandins, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF).  EDHF remains the least understood, because despite its central and potent role first described 25 years ago, EDHF has not been molecularly identified. Recent advances have demonstrated unequivocally that SK3 and IK1 (or SK4) channels play crucial roles in EDHF-mediated vasorelaxation, due in large part to their characteristic biophysical properties and sub-cellular localizations.

▼   Thomas M. Lincoln, Ph.D. 

Thomas M. Lincoln, Ph.D. Thomas M. Lincoln, Ph.D. 

Professor Emeritus

Ph.D.: University of Tennessee, Knoxville
Postdoctoral Studies: Vanderbilt University

Phone: 251-460-6428
Fax: 251-460-6967
tlincoln@southalabama.edu

Publications

Research Interests

Our laboratory is interested in the role of nitric oxide (NO) signaling and the mechanisms by which the second messenger, cyclic GMP, regulates vascular smooth muscle cell function. NO increases cyclic GMP that, in turn, activates a serine/threonine protein kinase, the cyclic GMP-dependent protein kinase (PKG).   We have identified several proteins whose phosphorylation is catalyzed by PKG in smooth muscle cells. More recently, we have found that NO and PKG regulate gene expression in vascular smooth muscle cells. Stable transfection or adenoviral gene delivery of the Type I PKG gene into vascular smooth muscle cells induces the expression of contractile proteins such as smooth muscle specific myosin and actin and repress the expression of extracellular matrix proteins such as osteopontin. DNA microarray analysis shows that over 100 genes appear to be regulated by PKG in smooth muscle. These results are pathophysiologically important because arterial vascular smooth muscle cells, in response to injury and atherosclerosis, lose their contractile phenotype and secrete extracellular matrix proteins. Hence, PKG appears to suppress the development of the atherosclerotic phenotype in vascular smooth muscle cells. More recently, we have observed that in response to injury and inflammatory cytokines, endogenous PKG mRNA expression is suppressed resulting in the loss of PKG protein in the vascular smooth muscle cells. These inflammatory conditions promote the modulation of vascular smooth muscle cells to the atherosclerotic phenotype. Restoration of PKG expression by adenoviral gene transfer restores the contractile, non-atherosclerotic phenotype. Therefore, one possible link between inflammation and fibroproliferative behavior of vascular smooth muscle cells in the suppression of PKG expression. We are currently studying the molecular mechanisms that control PKG mRNA and protein expression in vascular smooth muscle cells and would like to identify pharmacologic agents that increase PKG expression in these cells to prevent the modulation to the atherosclerotic phenotype. Clearly, adenoviral gene transfer of PKG cDNA into vascular lesions in vivo would be one mechanism using gene therapy for such vascular diseases as atherosclerosis, restenosis and inflammatory lesions.

▼   James C. Parker, Ph.D. 

James C. Parker, Ph.D. James C. Parker, Ph.D. 

Professor Emeritus

Ph.D.: University of Mississippi Medical Center
Postdoctoral Studies: University of Mississippi

Phone: 251-460-6826
Fax: 251-460-6464
jparker@southalabama.edu
 

Publications | Full CV [PDF]

Research Interests

A recent large scale clinical study demonstrated a 22% reduction in mortality of patients on mechanical ventilation for Acute Respiratory Distress Syndrome (ARDS) when tidal volume was reduced from the conventional 12 ml/kg to 6 ml/kg. This clinical study was based on previous animal experiments from our laboratory and others showing that alveolar overdistention produces microvascular injury and increased vascular permeability.  While previous hypotheses have proposed a "stretched pore" effect forcing open intracellular junctions or a "stress failure" limited by the tensile strength of the basement membrane, recently studies from our laboratory suggest that an active endothelial cell response to mechanical stress contributes significantly to the fluid and protein leak observed at high vascular and airway pressures. We have proposed that calcium entry through non-selective stretch activated cation channels (SACC) produces a necessary increase in cell calcium that triggers a permeability response utilizing many of the signal pathways involved in ligand mediated permeability increases. The Ca++ /calmodulin/myosin light chain kinase (MLCK) pathway has been implicated by studies showing that increased permeability in rat lungs due to lung overdistention was blocked by inhibition of either SACC,  Ca++ /calmodulin, or MLCK. Calcium transients in cultured pulmonary endothelial cells were also prevented by inhibition of SACC or MLCK. A possible role for tyrosine phosphorylation involved in focal adhesions has been suggested by isolated rat lung studies that demonstrate an enhanced susceptibility to mechanical injury after inhibition of protein tyrosine phosphatase and a reduced injury with inhibition of tyrosine kinase. Separation of epithelium and endothelium from basement membranes is a prominent feature of ventilator induced lung injury (VILI) in experimental animals suggesting a role of cell adhesion in this injury. During the tenure of  a recently awarded 5 year grant, we will explore the role of SACC using cultured endothelial cells from each vascular segment in the rat lung; artery, vein and microcirculation, with new methods for evaluating monolayer permeability under strain and pressure. A state-of-the art confocal microscope with multiple fluorochrome capability will be used. In addition, we have obtained the plasmid containing the MID1 gene from yeast which codes for the only SACC gene product cloned to date. The responses of native and transfected endothelial cells will be studied using fluorescent analysis of intracellular Ca++  and electrophysiologic response using single channel patch clamp methods. With these studies we hope to characterize the events which initiate and propagate increased vascular permeability secondary to mechanical stress and identify potential targets for pharmacological intervention in patients.

An additional recent direction in my laboratory has been the development of a perfluorocarbon liquid  ventilator in conjunction with Mallard Medical Co. of Redding, CA. This project is funded through the SBIR/STTR program of NIH and utilizes a patented method of liquid delivery through a bias flow mode that improves both gas exchange and fluid clearance from the lung compared to conventional tidal liquid ventilation. We are currently applying for Phase II funding and will finalize prototype designs for production. Controller algorithms are being developed for optimal control of tidal wave forms and automatic control of residual liquid volumes in the lung for efficient long term ventilation with minimal peak alveolar pressures.

▼   Sarah Sayner Ph.D. 

Sarah Sayner Ph.D. 

Assistant Professor

Ph.D.: University of South Alabama
Postdoctoral Studies: University of Cambridge England and University of South Alabama

Research Summary

The pulmonary endothelial barrier is critical to efficient gas exchange to supply the body with oxygen.  This single cells layer acts as a barrier restricting the flux of blood components from the vascular space into the underlying tissue.  Damage to the endothelial barrier is a characteristic feature of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

One of our areas of interest is compartmentalized cAMP signals in regulation of this pulmonary endothelial barrier.  While cAMP signals generated at the plasma membrane are barrier protective, cAMP signals generated in the cytosolic compartment by bacterial toxins are barrier disruptive.  We are further exploring compartmentalized cAMP signals by investigating the role of the recently identified mammalian soluble adenylyl cyclase (AC10 or sAC) in regulation of the endothelial barrier.  This enzyme is stimulated by bicarbonate to generate cytosolic cAMP, yet its role in the physiology of the endothelium is unknown.  Further, we are investigating how extracellular bicarbonate transits the plasma membrane to stimulate AC10.  Thus, our second area of interest is in bicarbonate transporters in the pulmonary endothelium.  We are interested in these transporters not only for the regulation of AC10, but we are also investigating how bicarbonate influx through these transporters affects intracellular pH.

▼   Mark S. Taylor, Ph.D. 

Mark S. Taylor, Ph.D. Mark S. Taylor, Ph.D. 

Associate Professor 

Ph.D.: Basic Medical Sciences, Department of Physiology, University of South Alabama
Postdoctoral Studies: Department of Pharmacology, University of Vermont College of Medicine

mtaylor@southalabama.edu

Recent Publications

Research Interests

Dynamic regulation of arterial tone influences blood pressure and flow, and ultimately plays a critical role in cardiovascular health and disease. My research focuses primarily on cellular signaling pathways that impair excitation-contraction coupling in vascular smooth muscle (VSM), thereby reducing contractility and promoting vasodilation.  In particular, I am interested in mechanisms that provide constant or tonic modulation of vascular tone by controlling membrane potential, intracellular Ca2+ and the sensitivity of the contractile apparatus to Ca2+.  My projects have investigated mechanisms of cyclic nucleotide vasorelaxation, including the pivotal roles of phosphodiesterases and cyclic nucleotide dependent protein kinases.  Recent studies using a novel class of cGMP-dependent protein kinase (PKG) inhibitors suggest a critical vasoregulatory role for constitutively active PKG in VSM.

The vascular endothelium (a single layer of cells lining the lumen of the entire vasculature) constantly modulates vascular tone.  I am currently studying the communication between the endothelium and smooth muscle, specifically the role of certain ion channels that influence this communication and alter vascular reactivity.  Of particular interest are certain small and intermediate conductance Ca2+-activated K+ channels (SK3 and IK, respectively) that elicit membrane potential hyperpolarization in endothelial cells.  These channels may exert fundamental regulation of vascular reactivity through tight control of endothelial function.  We recently showed that SK3-dependent hyperpolarization is communicated to adjacent smooth muscle, promoting vasodilation, and that the magnitude of this effect is dependent on the level of SK3 expression.  Expression levels of these channels may change considerably with hormonal status (i.e. with pregnancy) and pathological states, profoundly influencing cardiovascular function. Most recently, high-speed confocal imaging of arterial preparations has revealed dynamic and complex modes of Ca2+ signaling in the intact endothelium, opening exciting new areas for exploration. Future studies will investigate key factors modulating vascular tone and reactivity, including dynamic protein (i.e. SK3) expression, control of endothelial cell membrane potential and Ca2+, and mechanisms of communication between the endothelium and smooth muscle in health and disease. I employ various techniques and methodologies including arterial myography, confocal Ca2+ imaging, electrophysiology, molecular biology, immunohistochemistry, cell/tissue culture, and the use of genetic constructs.

▼   Mary I. Townsley, Ph.D. 

Mary I. Townsley, Ph.D. Mary I. Townsley, Ph.D. 

Professor and Senior Associate Dean

Ph.D.: University of California, Davis.
Postdoctoral Studies: University of South Alabama

Phone: 251-460-6815
Fax: 251-460-6386
mtownsley@southalabama.edu

Recent Publications

Research Interests

Research in my laboratory broadly focuses on mechanisms that regulate the integrity of the alveolar septal barrier in the lung and the pathobiology which leads to the development of acute lung injury. The role of lung endothelial heterogeneity with respect to calcium channel expression and regulation of endothelial barrier function are of particular interest. Our current work focuses on 1) the role of the vanilloid transient receptor potential calcium channel TRPV4 in acute lung injury, 2) intracellular localization of TRPV4 in lung endothelium in relation to focal adhesion plaques, and 3) the roles of TRPV4 and soluble epoxide hydrolase in modulating Pseudomonas aeruginosa-induced acute lung injury.  We have previously documented a key role for TRPV4 in mediating the acute lung injury evoked by challenge of lung with mechanical stress (high airway and high vascular pressure) or eicosatrienoic acids, epoxygenase derivatives of arachidonic acid. Techniques in the laboratory include: assessment of lung barrier function, endothelial permeability, lung histology and quantitative morphometry, immunohistochemistry, and calcium transients in lungs from intact animals.

▼   David S. Weber, Ph.D.

David S. Weber, Ph.D.David S. Weber, Ph.D.

Associate Professor

Ph.D.: Physiology, Medical College of Wisconsin
Postdoctoral Studies: Division of Cardiology, Emory University, Georgia; Department of Physiology, Medical College of Georgia and University of Michigan Medical School

dweber@southalabama.edu

Recent Publications

Research Interests  

Oxidative stress, defined as an increase in reactive oxygen species (ROS) in the vasculature, has been implicated in several pathologic conditions affecting the cardiovascular system including hypertension, atherosclerosis, and restenosis following balloon injury. Each of these conditions is associated with significant vascular damage and repair. Adjacent normal tissue facilitates the repair process and formation of neointima by both proliferation and migration. Several growth factors, including the potent platelet-derived growth factor (PDGF), stimulate vascular smooth muscle cell (VSMC) migration from the media to the neointima. Exposure of vascular smooth muscle cells to PDGF also results in generation of ROS, and ROS have been shown to have significant effects on both the growth and migration of vascular smooth muscle cells.

Therefore, the focus of my current studies is to test the hypothesis that ROS are critical mediators of VSMC migration. Two specific aims are being addressed; 1) to define signaling steps that mediate PDGF-induced VSMC migration and determine which are ROS sensitive, and 2) to define the contribution of ROS in vivo by studying migration and remodeling during restenosis following vascular injury in transgenic mice producing altered levels of ROS. These studies utilize several techniques including 1) the use of transwell migration assays using cultured VSMC following pharmacological interventions to examine mediators of migration, 2) immunoblotting, immunoprecipitation, and activity assays in cultured VSMC following pharmacological intervention or adenoviral infection to determine the redox-sensitivity of signaling mechanisms associated with migration, and 3) the use of transgenic mice that have VSMC-specific alterations in ROS levels to study the redox-sensitivity of signaling mechanisms during the process of restenosis induced by wire injury of the femoral artery.

▼   Xiangming Zha, Ph.D.

Xiangming Zha, Ph.D.Xiangming Zha, Ph.D.

Associate Professor 

B.Sc.: Shanghai JiaoTong University, 1991
M.Sc.: Shanghai Brain Research Institute, 1994
Ph.D.: University of Iowa, 2000
Postdoc: University of Iowa, with Drs. Steven Green and Michale Dailey, and University of Iowa and HHMI, with Dr. Michael J. Welsh

Phone: (251) 460 6769
Fax: (251) 460 6771
Email: zha@southalabama.edu

Research Interests

Acid signaling and Neuronal Function

While brain pH is tightly regulated, it can fluctuate under physiological and pathological conditions.  In particular, various disease conditions, including seizure, stroke, mitochondrial dysfunction and neurodegenerative diseases, all lead to a decrease in extracellular pH, or acidosis.  Understanding how a reduced pH regulates neuron function thus has important clinical implications.

There are currently three main focuses in the laboratory. First, we are asking how protons, through activating acid-sensing ion channels and G-protein coupled receptors, signal in neurons. Second, we are asking how acid signaling regulate neuron function and behavioral output in rodents. Third, we are asking how a change in acid signaling alters acidosis- and ischemia-induced neuronal injury. In these studies, we use cell lines, primary neuron cultures, organotypic brain slices and whole animals, and apply a combination of cellular, molecular, biochemical, electrophysiological and imaging approaches.

Selected Recent Publications

  1. Jiang N*, Wu J*, Leng T*, Yang T, Zhou Y, Jiang Q, Wang B, Hu Y, Ji YH, Simon RP, Chu XP, Xiong ZG#, and Zha XM#. Region specific contribution of ASIC2 to acidosis- and ischemia-induced neuronal injury. J Cereb Blood Flow Metab 2016. published online Feb 9, 2016. (# co-corresponding author). Online Access
  2. Wu J*, Leng T*, Jing L, Jiang N, Chen D, Hu Y, Xiong ZG, and Zha XM. Two di-leucine motifs regulate surface expression and dendritic targeting of mouse ASIC2a. Mol. Brain 9(1): 9, 2016. Free Access
  3. Wu J, Xu Y, Jiang YQ, Xu J, Hu Y, and Zha XM. ASIC subunit ratio and differential surface trafficking in the brain. Mol. Brain 9(1): 4, 2016. Free Access
  4. Huang Y, Jiang N, Li J, Ji YH, Xiong ZG#, Zha XM#. (2015) Two aspects of ASIC function: synaptic plasticity and neuronal injury (review). Neuropharmacology 94:42-8. (# co-corresponding author) Online Access
  5. Du J, Reznikov LR, Price MP, Zha XM, Lu Y, Moninger TO, Wemmie JA, and Welsh MJ. (2014) Protons and ASICs are a neurotransmitter/receptor pair that regulates synaptic plasticity in the lateral amygdala. Proc. Natl. Acad. Sci. 111:8961-6. Free Access
  6. Jing L, Chu XP#, and Zha XM#. Three distinct motifs within the C-terminus of ASIC1a regulate its surface trafficking. Neuroscience 247:321-7, 2013. (#co-corresponding author). Free Access
  7. Zha XM. Acid-sensing ion channels: trafficking and synaptic function. (review). Mol. Brain 6:1, 2013. Free Access
  8. Jing L*, Chu XP*, Jiang YQ*, Collier DM, Wang B, Jiang Q, Snyder PM and Zha XM. (2012) N-Glycosylation of Acid-sensing Ion Channel 1a Regulates its Trafficking and Acidosis-induced Spine Remodeling. J Neurosci. 32: 4080-91. Free Access
  9. Jing L, Jiang YQ, Jiang Q, Wang B, Chu XP, and Zha XM. Interaction between the first transmembrane domain and the thumb of ASIC1a is critical for its N-glycosylation and trafficking. PLoS One 6:e26909, 2011. Free Access
  10. Zha XM, Costa V, Harding A, Reznikov L, Price MP, Benson CJ, and Welsh MJ. ASIC2 subunits target acid-sensing ion channels to the synapse via an association with PSD-95. J Neurosci. 29: 8839-46, 2009. Free Access
  11. Zha XM, Wang R, Collier DM, Wemmie JA, Snyder P, and Welsh MJ. (2009) Oxidant Regulated Intersubunit Disulfide Bond Formation between ASIC1a Subunits. Proc. Natl. Acad. Sci. 106: 3573-3578. Free Access 

Current Lab Members

Mindi He (postdoctoral fellow)
Yuanyuan Xu (visiting scholar)

Past Lab Members

Visiting scholars: Junjun Wu, Nan Jiang, Yuqing Jiang, Lan Jing
Postdoctoral fellow: Yufan Zhou
Undergraduate students: Tian Tan, Thomas George 

 

Adjunct Faculty

Gerd Heusch, Prof. Dr. med., Dr. h.c. 
Direktor des Institutes für Pathophysiologie
Zentrum für Innere Medizin
Universitätsklinikum Essen
Essen, Germany
gerd.heusch@uni-essen.de 

Thomas Krieg, Dr. med.
Clinical Pharmacology Unit
University of Cambridge
Addenbrooke’s Hospital
Cambridge CB2 2QQ, UK
tk382@medschl.cam.ac.uk 

Derek Yellon, Ph.D., D.Sc. 
Department of Academic & Clinical Cardiology
University College Hospital London, England
d.yellon@ucl.ac.uk 

Marilyn P. Merker, Ph.D.
Medical College of Wisconsin
Dept. Veterans Affairs
VAMC Milwaukee, WI
mmerker@mcw.edu

Staff Directory

Kelli Roberson
Grants Admin. Specialist I 
kroberson@southalabama.edu 

Penny Cook
Department Manager
pcook@southalabama.edu