Research Goals and Interests
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.
Dual perforated -cell patch and dual whole cell patch are used to test channel behaviors under defined ionic conditions (whole cell). A variety of probes of well known size and charge are used to probe the permeation path for molecular sizes predicted for many second messenger molecules.
We have also generated a number of mutants of Cx43 and Cx37 in an attempt to delineate at the molecular level the moieties responsible for the permselectivity properties of gap junction channels. More recently we have begun to study mutants that occur naturally in the environment that are associated with specific disease conditions for Cx43 and Cx26.
Lacrimal gland secretions
The lacrimal gland is a major source of fluid to the surface of the eye. Diseases such as dry eye are caused by reduced tear flow to the surface of the eye. The transport of solutes across the epithelium of the lacrimal gland generates tear fluid and is therefore potentially the major site in causing dry eye. We use knockout mice to study the affect of a specific genes on fluid production as well as mouse models which result in a similar condition to dyr eye in mice . Our efforts have centered on elucidating the mechanism of fluid transport across the epithelium which makes up the secretory portion of the lacrimal gland. Indivdual cells are isolated and patch clamped under a variety of conditions for wild type mice, knockout and NZB mice. Our results indicate that in diseased mice lacrimal acinar cells Ach induced anion currents are minimal or reversed in sign relative to their wild type counterparts. In addition, the disease animals under non-stimulated conditions are under the influence of a partially activated PKC pathway that is able to modulate the resting conductances and might well be a participant in the altered ACh response of the NZB lacrimal cells. The whole cell conductances associated with fluid production are unaffected by the PKA pathway. This work is done in collaboration with Drs. Ben Walcott and Leon Moore.
Reprints
"Cardiac Gap Junction Channels Show Quantitative Differences in Selectivity"
"Selective permeability of gap junction channels"
"Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers"
"Connexin-specific cell-to-cell transfer of short interfering RNA by gap junctions"
Recent publications
2004 Plotnikov,A.N., E.A. Sosunov, J. Qu, I. Shlapakova, E.P. Anykhovsky, L.Liu, M.J. Janse, P.R. Brink, I.S. Cohen, R.B. Robinson, P. Danilo and M.R. Rosen, "Biological Pacemaker Implanted in Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiologically Acceptable Rates", Circulation 109:506-512
2004 Goldberg, G., V. Valiunas, and P.R. Brink, "Selectivity Permeability of Gap Junction Channels", Biochem, Biophysica Acta 662:96-101
2004 Gemel, J., V. Valiunas, P. R. Brink, and E. C. Beyer, "Connexin43 and connexin26 form gap junctions, but not heteromeric channels in co-expressing cells", J.Cell Sci. 117:2469-2480
2004 Virginijus Valiunas, Sergey Doronin, Laima Valiuniene, Irina Potapova, Joan Zuckerman, Benjamin Walcott, Richard B. Robinson, Michael R. Rosen, Peter R. Brink and Ira S.Cohen, "Human mesenchymal stem cells make cardiac connexins and form functional gap junctions", Journal of Physiology: 555:617-626
2004 Potapova I., A. Plotnikov, Z. Lu, P. Danilo, V. Valiunas, J. Qu, S. Doronin, J. Zuckerman, I. Shlapakova, J. Gao, Z. Pan, A. Herron, R.B. Robinson, P.R. Brink, M.R. Rosen and I.S. Cohen, "Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers", Circulation Research: 94:952-959
2004 Mese, G., E. Londin, R. Mui, P.R. Brink and T.W. White, "Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss", Human Genetics: 115:191-199
2004 Valiunas V., R. Mui , E. McLachlan , G. Valdimarsson , P.R. Brink and T.W. White, "Biophysical characterization of zebrafish connexin35 hemichannels", Am. J. Physiol. Cell Physiol. 287:C1596-C1604
2004 Rosen, M., P.R. Brink, I. Cohen, and R. Robinson, "Cardiac Pacemakers for the New Millennium", Hellenic J. Cardiology 45:205-207.
2004 Rosen, M.R., P.R. Brink, I. Cohen, and R. Robinson, "Genes, stem cells and biological pacemakers", Cardiovascular Research 64:12-23
2004 White, T.W., H. Wang, R. Mui, J. Letteral and P.R. Brink, "Cloning and functional expression of invertebrate connexins from Halocynthia pyriformis", FEBS Letters 577:42-48
2005 Rosen, M., P.R. Brink, I.S. Cohen and R.B. Robinson, "Adult Human Stem Cells as a Platform for Gene Therapy: Fabricating a Biological Pacemaker", Discovery Medicine 5:18-24
2005 Walcott, B., A. Birzgalis, L.C. Moore and P.R. Brink, "Fluid secretion and the Na+- K+-2C1- cotransporter in mouse exorbital lacrimal gland", Am. J. Physiol. Cell Physiol. 289:C860-C867
2005 Valiunas, V., J.F. Bechberger, C.C. Naus, P.R. Brink and G.S. Goldberg, "Non-Transformed Cell can Normalize Gap Junctional Communication with Transformed Cells". BBRC 33:179-
2005 Wang, M., A.D. Martinez, V.M. Berthoud, K.H. Seul, V. Valiunas, S. Kumari, P.R. Brink and E.C. Beyer, "Connexin43 with a Cytoplasmic Loop Deletion Inhibits the Function of Several Connexins", BBRC 333: 1185-1193
2005 Valiunas, V., Y. Polosina, H. Miller, I. Potapova, L. Valiuniene, S. Doronin, R.T. Mathias, R.B. Robinson, M.R. Rosen, I.S. Cohen, and P.R. Brink, "Connexin-specific cell- to-cell transfer of short Interfering RNA by gap junctions", J. Physiol 568:459-468
2005 Cohen I.S., P.R. Brink, R.B. Robinson and M. R. Rosen, "The why, what, how and when of biological pacemakers", Nature Clinical Practice Cardiovascular Medicine 2:374-375
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", Optics Letters 30:2263-2265
2005 Ramanan, S.V., V. Valiunas and P.R. Brink, "Non-Stationary Fluctuation Analysis of Macroscopic Gap Junction Channel Records", J. Membrane Biol. 205:81-88
2006 Brink, P.R., V. Valiunas, H.Z. Wang, W. Zhaoo, K .Davies, and G.J. Christ, "Experimental Diabetes Alters Connexin43 Derived Gap Junction Permeability in Short-Term Cultures of Rat Corporeal Vascular Smooth Muscle Cells", J. Urology 175:381-386
2006 Robinson, R.B., P.R. Brink, I.S. Cohen and M.R. Rosen, "I9f) and the Biological Pacemaker", Pharmacological Research (in press)
Comments to Peter.Brink@stonybrook.edu