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Paul A Welling
 

Paul A Welling M.D.

Academic Title: Professor
Primary Appointment: Physiology
Additional Title(s): Graduate Program Director
pwelling@umaryland.edu
Location: 655 West Baltimore St., BRB 5-029
Phone: 410-706-3851
Fax: 410-706-8341
Lab: 410-706-2653

Personal History:

  • 1988: M.D., University of Kansas Medical School 
  • 1993: Fellow, Yale University Medical School, Cell and Molecular Physiology 
  • 1993-99: Assistant Professor, University of Maryland Medical School 
  • 1999-2001: Established Investigator, American Heart Association 
  • 1999-2006: Associate Professor, University of Maryland Medical School 
  • 2003: Fellow of the American Heart Association 
  • 2006-present: Professor, University of Maryland Medical School
  • 2010: Teacher of the Year, Graduate Program in Life Sciences, University of MD
  • 2011: Arthur Guyton Distinguished Lectureship, Association of Chairs of Departments of Physiology
  • 2013: Fred Samsom Memorial Lecturer, University of Kansas Medical School
  • 2014: Steven Hebert Distinguished Lectureship, American Physiological Society

Research Interests:

The Welling laboratory studies the molecular genetics and physiology of electrolyte transport disorders. The movement of ions across cell membranes is exquisitely controlled for a diverse variety of vital body functions. The normal electrical activity of nerve and brain cells, the control of blood pressure by the kidney and the maintenance heart rhythm represent just a few examples. Defects in ion transport molecules and their regulators give rise to serious, even lethal, human diseases. A major thrust of investigations in the Welling laboratory involves molecular genetic dissections of inherited disorders of membrane transport, so-called “channelopathies” or “transporteropathies.”

We are particularly interested in understanding the regulatory mechanisms which normally control the number, location and activity of transport molecules and that go awry in human disease. We employ a multidisciplinary approach, combining tools of molecular genetics, cellular biology, biochemistry, and physiology with state-of-the-art imaging techniques. A key strategy involves defining regulator or localization signals that are embedded within the structures of ion channels and salt-transporters; discovering the intracellular machinery that decodes the signals; and understanding the molecular signaling pathways that influence the interaction between the two. Genetically modified animal models are used to translate our discoveries about fundamental mechanisms to higher-level systems in vivo.

Our focus has been on understanding how potassium channels in the heart, kidney and nervous system are regulated in health and dysfunction in disease, providing ideal models to investigate fundamental molecular mechanisms with direct clinical impact. One research program is focused on unraveling the mechanisms that control salt balance and blood pressure in health and contribute to electrolyte disorders and hypertension in kidney disease. Our studies in the heart are leading to a molecular understanding of certain hereditary arrhythmias. 

Research Topics

Physiology, Systems Biology and Pathophysiology 

  • Ion Channels and Transporters 
  • Molecular Genetics of Membrane Transport and Excitability Disorders 
  • Molecular Mechanisms of Trafficking Defects in Cardiac Arrhythmias 
  • Molecular and Cell Biology of the Kidney 
  • Regulation of Salt Balance and Blood Pressure 
  • Hypertension 

Molecular & Cellular Biology

  • Cell Signaling 
  • Endocytosis 
  • Exocytosis 
  • Mechanisms of Cell Polarity
  • Regulation of Membrane Trafficking 
  • Scaffolding Proteins 
  • Secretory Pathway

Lab Techniques and Equipment:

Recombinant DNA techniques, including cloning, mutagenesis and heterologous expression, are used extensively. Protein-Protein interactions are studied using recombinant protein biochemistry, yeast two hybrid techniques and proteomic approaches. We also employ a most state-of-the art cell biological techniques, including confocal microscopy. Functional genomic approaches such as DNA microarrays are becoming a mainstay. We employ a wealth of electrophysiological techniques, such as patch-clamp analysis (single channel and whole cell), two-microelectrode voltage clamp, and epithelial monolayer voltage clamp.


Publications:

Recent Representative Publications

Yoo D, Fang L, Mason A, Kim BY and Welling PA. A phosphorylation-dependent export structure in ROMK (KIR 1.1) channel overrides an ER- localization signal. J Biol Chem. 2005;280(42):35281-9.

Wade JB*, Fang L*, Liu J*, Li D*, Yang CL†, Subramanya AR†, Maouyo D*, Mason A*, Ellison DE†, and Welling PA* WNK1 Kinase Isoform Switch Regulates Renal Potassium Excretion, Proc. Natl. Acad. Sci. USA, 2006. 30;103(22):8558-63.  PMCID: PMC1482529

Alewine C*, Olsen O*, Wade JB, Welling PA, TIP-1 has PDZ Scaffold Antagonist Activity, Mol Biol Cell. 2006 Oct;17(10):4200-11  PMCID: PMC1635354

Ma D, Tang S, Rogers T, Welling PA, The Andersen-Tawil Syndrome Mutant Kir2.1 (V302M) Alters the G-loop cytoplasmic K+ Conduction Pathway, J Biol Chem, 2007;282(8):5781-9

Olsen O, Funke L, Long J-F, Fukata M, Kazuta T, Trinidad JC, Moore KA, Misawa H, Welling PA, Burlingame AL, Zhang M, and Bredt DS. Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice, J. Cell Biol. 2007 179(1):151-64  PMCID: PMC2064744

Alewine C, Kim BY, Hegde V and Welling PA, Basolateral Membrane Expression of Kir 2.3 Requires Lin-7 L27 Domain Interaction With A Polarized Scaffold, Am J Physiology, Cell 2007 Dec;293(6):C1733-41.

Mason AK, Jacobs BE, Welling PA AP-2 Dependent Internalization of Kir2.3 Is Driven By A Non-Canonical Di-Hydrophobic Signal, J Biol Chem, 2008 Mar 7;283(10):5973-84

Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim JD, Subramanya AR, Steinle NI, Parsa A, Ober CC, Welling PA, Chakravarti A, Weder AB, Cooper RS, Mitchell BD, Shuldiner AR, Chang YP. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31. PMCID: PMC2629209

Subramanya AR, Wade JB, Welling PA, WNK4 Kinase Diverts Newly Synthesized NCC Cotransporters into the Lysosomal Pathway and Stimulates AP-3 Clathrin Adaptor Interaction, J Biol Chem. 2009 Apr 28. 2009 Jul 3;284(27):18471-80.  PMCID: PMC2709348

Fang L, Kim BY, Wade JB, Welling PA, The ARH Adaptor Protein Targets the Kidney ROMK Potassium Secretory Channel for Endocytosis, Journal of Clinical Investigation, 2009 Nov;119(11):3278-89.  PMCID: PMC2769171

Fang L, Li D and Welling PA, Hypertension Resistance Polymorphisms in ROMK Alter Channel Function by Different Mechanisms, Am J Physiol Renal Physiol. 2010 Dec;299(6):F1359-64.  PMCID: PMC3006317

Wade JB, Fang L, Coleman RA, Liu J, Grimm PR, Wang T, Welling PA. Differential Regulation of ROMK(Kir1.1) in Distal Nephron Segments by Dietary Potassium, Am J Physiol Renal Physiol 2011 Jun;300(6):F1385-93.  PMCID: PMC3119145

Donghui M, Taneg, TK, Kim BY, Hagen B, Lederer WJ , Welling PA.  Golgi Export of the Kir2.1 Channel is Driven by a Trafficking Signal Located within its the Tertiary Structure, Cell. 2011 Jun 24;145(7):1102-15.  PMCID: PMC3139129

Ortega B, Mason AK, Welling PA. A tandem Di-hydrophobic motif mediates clathrin-dependent endocytosis via direct binding to the AP-2 ασ2 subunits. J Biol Chem. 2012 Aug 3;287(32):26867-75. doi: 10.1074/jbc.M112.341990. Epub 2012 Jun 18.  PMCID: PMC3411023

Grimm PR, Taneja TK, Liu J, Coleman R, Chen YY, Delpire E, Wade JB, Welling PA. SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem. 2012 Nov 2;287(45):37673-90. doi: 10.1074/jbc.M112.402800. Epub 2012 Sep 12.  PMCID: PMC3488044

Welling, PA. Molecular Mechanisms of Potassium Secretion. Seminars in Nephrology, 33(3), May 2013, pp215-228

Zhou X, Zhang Z, Shin MK, Horwitz SB, Levorse JM, Zhu L, Sharif-Rodriguez W, Streltsov DY, Dajee M, Hernandez M, Pan Y, Urosevic-Price O, Wang L, Forrest G, Szeto D, Zhu Y, Cui Y, Michael B, Balogh LA, Welling PA, Wade JB, Roy S, Sullivan KA. Heterozygous Disruption of Renal Outer Medullary Potassium Channel in Rats is Associated With Reduced Blood Pressure. Hypertension. 2013

Welling, PA. Regulation of Potassium Channel Trafficking in the Distal Nephron. Curr Opin Nephrol Hypertens. 2013 Sep; 22 (5): 559-65

Srivastava, Shalabh; Li, Dimin; Edwards, Noel; Hynes, Ann Marie; Wood, Katrina; Al-Hamed, Mohamed; Wroe, Anna; Reaich, David; Moochhala, Shabbir; Welling PA; Sayer, John, Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity" Physiological Reports, Nov;1(6):e00160. doi: 10.1002/phy2.160. Epub 2013 Nov 19.  PMCID: PMC3871474

Welling, PA. Rare Mutations in Renal Sodium and Potassium Transporter Genes Exhibit Impaired Transport Function, Curr Opin Nephrol Hypertens. 2014 Jan;23(1):1-8. PMID: 24253496

Kolb, AR, Needham PG, Rothenberg C, Welling PA, and Brodsky JL. ESCRT regulates surface expression of the Kir2.1 potassium channel, Mol Biol Cell. 2014 Jan;25(2):276-89. doi: 10.1091/mbc.E13-07-0394. Epub 2013 Nov 13.PMID: 24227888.  PMCID: PMC3890348