Peter R. Brink

Research

Intercellular Communication: Gap Junctions

The research efforts are focused on the connexins of cardiac myocytes and vascular smooth muscle cells. They are all thought to be essential to processes such as developed vaso-motor tone and cardiac arrhythmias. A variety of methods are used to monitor permselectivity and gating of homotypic, heterotypic and heteromeric forms. We are also interested in delineating the integration of exogenously placed stem cells into tissues and role gap junction channels play. To assist us in defining the types of connexins expressed in tissue we use both immuno-staining and Western blotting.Since his initial observations he has characterized the gating of gap junction channels as well as their permselectivity to higher molecular weight substances. Recently he has demonstrated that small interfering RNA, a molecule of 4 kD, can permeate gap junctions and silence expression of target proteins in electrically connected cells. In 2003 he began his research studies on gap junction channels in human mesenchymal stem cells, in collaboration with Drs. Ira Cohen, Mike Rosen and Richard Robinson, where he demonstrated they expressed and trafficked both connexin43 and connexin40 and made gap junctions with cardiac myocytes. He also has been active in studies of stem cell homing and stem cells as the delivery system for creating a biological pacemaker. In 2009 he oversaw a project that used hMSCs to carry pacemaker genes to isolated canine ventricular myocytes demonstrating that the two cell functional syncytium was a biological pacemaker.

Selected
Publications

2005 Cohen I.S., P.R. Brink, R.B. Robinson and M. R. Rosen. "The why, what, how and when of biological pacemakers." Nature Clin Pract Cardiovasc Med 2:374-75

2005 Pan Y.T., Q. Wu, Z.G. Wang, P.R. Brink and C.W. Cu. "High-resolution imaging characterization of bladder dynamic morphophysiology by time-lapse optical coherence tomography." Opt. Let. 30:2263-2265

2005 Ramanan, S.V., V. Valiunas and P.R. Brink. "Non-stationary fluctuation analysis of macroscopic gap junction channel records." J. Memb. Biol. 205:81-88

2006 Brink, P.R., V. Valiunas, HZ Wang, W. Zhaoo, K .Davies, and G.J. Christ. "Experimental Diabetes alters Connexin43-derived gap junction permeabilitiy in short term cultures of rat corporal vascular smooth muscle cells." J. Urology 175:381-386

2006 Robinson, R.B., P.R. Brink, I.S. Cohen and M.R. Rosen. "If and the biological pacemaker." Pharmacological Research 53:407-415

2006 Wang, HZ., P.R. Brink, G.J. Christ. "Gap junction channel activity in short-term cultured human detrusor myocyte cell pairs: gating and unitary conductance." Am .J. Physiol. 291:C1366-1C1376

2006 Bucchi A., A.N. Plotniko, I Shalapakova, P. Danilo, Y. Kryukova, J. Qu, Z. Lu, Z. Pan, I. Potapova, B. McKinght, S. Girouard, I.S. Cohen, P.R. Brink, R.B. Robinson, and M.R. Rosen. "Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker." Circulation 114:986-988

2007 Potapova, I., G. Gaudette, P.R. Brink, R.B. Robinson, M.R. Rosen, I.S. Cohen, and SV Doronin. "Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation and survival of endothelial cells in vitro." Stem Cells 25:2128-2138 Eup March 29

2007 Yum, S., J. Zhang, V. Valiunas, G. Kanaporis, P.R. Brink, T. White, and S. Scherer. "Human connexins26 and connexin30 form functional heteromeric and heterotypic channels." AJP 293:1032-1048 2007

2007 Rosen, M.R., P.R. Brink, I.S. Cohen, and R.B. Robinson. "Biological pacemakers based on If." Med Biol Eng Comput. 45:157-166

2007 Rosen A.B., Kelly D.J., Schuldt A.J., Lu J, Potapova I.A., Doronin S.V., Robichaud K.J., Robinson R.B., Rosen M.R., Brink P.R., Gaudette G.R., Cohen I.S. "Finding fluorescent needles in the cardiac haystack: tracking human mesenchymal stem cells labeled with quantum dots for quantitative in vivo three-dimensional fluorescence analysis." Stem Cells. 2007 Aug;25(8):2128-38. Epub 2007 May 10.

2007 Potapova, I., S Doronin, D Kelly, A Rosen, A Schuldt, Z Lu, Y Guo, P. Kochupura, R Robinson, MR Rosen, PR Brink, GR Gaudette, IS Cohen. "Replacing damaged myocardium." J. Electrocardiol. 40: S199-201

2007 Plotnikov, A., Shlapakova, L., Szaboles, M., Danilo, P., Lorell, B., Potapova, I., Lu, Z., Rosen, A., Mathias, R., Brink, P., Robinson, R., Cohen, I., Rosen ,M. "Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart." Circulation 116:706-13

2008 Potapova, I., Brink, P.R., Cohen, I.S., Doronin, S.V. "Culturing of human mesenchymal stem cells as 3D-aggregates induces functional expression of CXCR4 that regulates adhesion to endothelial cells." J. Biol. Chem. 283:13100-7

2008 Kanaporis, G, Mese, G., Valiuniene, L., White T.W., Brink, P.R., Valiunas, V. "Gap junction channels exhibit connexin-specific permeability to cyclic nucleotides." J.Gen Physiol. 131: 293-305

2008 Mese, G, V. Valiunas, P.R. Brink, T.W. White. "Connexin26 deafness associated mutations show altered permeability to large cationic molecules." Am. J. Physiol. 295:C966-C974

2008 Potapova IA, Doronin SV, Kelly DJ, Rosen AB, Schuldt AJ, Lu Z, Kochupura PV, Robinson RB, Rosen MR, Brink PR, Gaudette GR, Cohen IS. "Enhanced recovery of mechanical function in the carine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage." Am. J. Physiol. 295:H2257-H2263.

2008 Nguyen, L., Rebecchi, M., Moore, L., Glass, P., Brink, P.R., Lui, L. "Attenuation of isoflurane-induced preconditioning and reactive oxygen species production in the senescent rat heart." Anesth Analog 107:776-782

2008 Rosen, M.R., Brink, P.R., Cohen, I.S., Danilo, P. Jr., Robinson, R.B., Rosen, A.B., Szabolcs, M.J. "Regenerative therapies in electrophysiology and pacing." J. Interv. Card Electrophysiol. 2:87-98

2009 Kelly DJ, Rosen AB, Schuldt AJ, Kochupura PV, Doronin SV, Potapova IA, Azeloglu EU, Badlyak SF, Brink PR, Cohen IS, Gaudette GR. "Increased Myocyte Content and Mechanical Function Within a Tissue-Engineered Myocardial Patch Following Implantation." Tissue Eng. Part A:15:2189-2201

2009 DeRosa, A., G. Mese, L. Li, C. Sellitto, PR. Brink, X. Gong, TW White. "The cataract causing Cx50-S50P mutant inhibits Cx43 and intercellular communication in the lens epithelium." Exp Cell Res. 315:1063-1075

2009 Liu,, L., J. Zhu, P.S. Glass, P.R Brink, I.J. Rampil, M.J. Rebecchi. "Age-associated changes in cardiac gene expression after preconditioning." Anesthesiology 111:1052-1064

2009 Bai, Y., R.T. Mahon, J.C. White, P.R. Brink, K.H. Chon. "Impairment of the autonomic nervous function during decompression sickness in swine." J. Appl. Physiol. 106:1004-1009

2009 Valiunas, V., G. Kanaporis, L. Valiuniene, C Gordon, H. Wang, L. Li, RB. Robinson, MR. Rosen, IS. Cohen, PR. Brink. "Coupling an HCN2 expressing cell to a myocyte creates a two cell pacing unit." J. Physiol. 587:5211-5226

2010 Zhu, J., M. Rebecchi, M. Tan, P. Glass, PR Brink, L. Lui. "Age-associated differences in activation of AKt/GSK-3beat signaling pathways and inhibition of mitochondrial permeability transition pore opening in the rat heart." J. Gerontol A boil Sic Med Scie 65:611-619.

2010 Brink, PR., RB Robinson, MR Rosen, IS Cohen. "In vivo cellular delivery of siRNA" IDrugs 13(6):383-387

2011 Brink, PR., Valiunas, V., Gordon, C, Rosen MR., Cohen, IS. Can gap junctions deliver? Biochem Biophys Acta Epub PMID 21986484 2011 Kanaporis, G., Brink PR., Valiunas, V., Gap junction permeability: selectivity for anionic and cationic probes. Am. J.Physiol. 300: C600-C609

2012 Gao., J., Sun, X., Moore, LC., Brink, PR. White, TW., Mathias, RT. The effect of size and species on lens intracellular hydrostatic pressure IOVS: 54:183-192 2012 Lu, J., Wang HZ., Jia, Z., Lu, Z., Guo, Y., Boink, GJ., Brink, PR., Robinson, RB., Encheva, E., Cohen, IS.
Improving cardiac conduction with a skeletal muscle sodium channel by gene and cell therapy. J. Cardiovasc. Pharmacol., 60:88-99

2013 Singer DD, Singer AJ, Gordon C, Brink P, The effects of rate mesenchymal stem cells on injury progression in a rat model. Acad. Emerg Med 20: 398-402

2013 Kaufmann, J., Gordon, C., Bergamaschi, R., Wang, ZH., Cohen, IS., Valiunas, V., Brink, PR., The effects of the histone deacetylase inhibitor 4-phenylbutryrate on gap junction conductance and permeability. Frontiers in Pharmacology 4: article 111 1-7

2013 Mayan, M., Gago-Fuentes, R., Carpintero-Fernandez, P., Fernandez-Puente, P., Filgueira-Fernandez, P., Goyanes, N., Valiunas, V., Brink, PR., Goldberg, G., Blanco, F. Articular chondrocyte network mediated by gap junctions: role in metabolic cartilage homeostasis. Ann Rheum Dis 74(1): p. 275-84.

2014 Gago-Fuetes, R., Carpinintero-Fermandez, P., Goldbring, MB. Brink, PR., Mayan, D., Blanco, F. Biochemical evidence for gap junctions and Cx43 expression in immortalized human chondrocyte cell line: a potential model in the study of cell communication in human chondrocytes. Osteoarthritis Cartilage. 22:586-590

2014 Chauveau, S., Brink. PR., Cohen, IS. Stem cell-based biological pacemakers from proof of principle to therapy; a review Cytotherapy 16:873-880

2015 Valiunas, V., H.Z. Wang, L. Li, C. Gordon, L. Valiuniene, I.S. Cohen, and P.R. Brink, A comparison of two cellular delivery mechanisms for small interfering RNA.Physiol Rep, 3(2).