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Adam J. Smolka Ph.D.

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Rank
  • Professor
College
  • College of Medicine
Department
  • Medicine
Academic Focus
  • Pathophysiology of Helicobacter pylori
  • Biochemistry, cell biology and pharmacology of gastric acid secretion
  • Interaction of gastric and colonic microbiomes in maintaining health

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Biography

Publication Highlights

Saha A, Backert S, Hammond CE, Gooz M, Smolka AJ. Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology. 2010 Jul;139(1):239-48. PubMed PMID: 20303353; PubMed Central PMCID: PMC2902712.

 

Saha A, Hammond CE, Beeson C, Peek RM Jr, Smolka AJ. Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa. Gut. 2010 Jul;59(7):874-81. PubMed PMID: 20581234; PubMed Central PMCID: PMC2980826.

 

Zhang YM, Noto JM, Hammond CE, Barth JL, Argraves WS, Backert S, Peek RM Jr, Smolka AJ. Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase a-subunit gene expression by miRNA. Am J Physiol Gastrointest Liver Physiol. 2014 Apr 1;306(7):G606-13. PubMed PMID: 24503769; PubMed Central PMCID: PMC4116396.

 

Hammond CE, Beeson C, Suarez G, Peek RM Jr, Backert S, Smolka AJ. Helicobacter pylori Virulence Factors Affecting Gastric Proton Pump Expression and Acid Secretion. Am J Physiol Gastrointest Liver Physiol. 2015 Jun 4;PubMed PMID: 26045613.

Contributions to Science

Before enrolling in graduate school in 1979, I gained extensive research experience with electrophoretic techniques that offered advantages for bioseparation processes in the microgravity environment of Earth orbit. I studied isolation of gammaglobulins from extracorporeal blood circulation using forced-flow electrophoresis (University of Edinburgh Veterinary School,1969-72); isotachophoresis and isoelectric focusing of cells as separative processes in zero gravity (University of Arizona Engineering Experiment Station, 1973-1976); and electrophoretic cell separation using microspheres (Space Sciences Laboratory, Marshall Space Flight Center, Huntsville, Alabama, 1977-1979). I was afforded unusual independence for a predoctoral researcher, but also benefited enormously from close mentorship, primarily by Dr. Milan Bier, the renowned electrophoresis theoretician and NASA bioseparations consultant. In 1975, I contributed blood samples and loaded the MA-011 isotachphoresis module prior to launch on the Apollo-Soyuz orbital mission. My early papers (see below), were the first to report bulk electrophoretic isolation of human gammaglobulin, and the use of immunomicrospheres to separate cell populations with overlapping electrophoretic mobility profiles.

a.     Smolka AJ, Logan EF. Recovery of immunoglobulin G from Cohn fraction II + III by forced flow electrophoresis. Prep Biochem. 1972; 2:329-345. PubMed PMID: 4117266.

b.     Bier M, Smolka AJ, Kopwillem A. Preparative electrophoresis in zero gravity. J Colloid Interface Sci. 1976; 55:197-207.

c.     Smolka AJ, Margel S, Nerren BH, Rembaum A. Electrophoretic cell separation by means of microspheres. Biochim Biophys Acta. 1979 Dec 3;588(2):246-55. PubMed PMID: 116687.

d.     Smolka AJ, Kempner DH, Rembaum A. Electrophoretic separation of human lymphocytes by means of immunomicrospheres. Electrophoresis. 1982; 3:300-305.

Dr. George Sachs, discoverer of the gastric H,K-ATPase responsible for acid secretion, recruited me from NASA to the physiology PhD program at UAB. My dissertation described creation and characterization of the first monoclonal antibodies against H,K-ATPase alpha subunit and discovery of secretagogue-induced H,K-ATPase translocation from parietal cell tubulovesicles to the secretory canaliculus. My postdoctoral and subsequent research as an NIH-funded P.I., first at UCLA and later at MUSC, leveraged the epitope specificity of monoclonal and site-directed polyconal antibodies to gain insight into H,K-ATPase expression, membrane topology, gastric and renal localization, and function, as documented below. These antibodies have been utilized in innumerable gastric physiology studies world-wide through licensing agreements with EMD Millipore Corp.

a.     Smolka A, Helander HF, Sachs G. Monoclonal antibodies against gastric H+ + K+ ATPase. Am J Physiol. 1983 Oct;245(4):G589-96. PubMed PMID: 6312812.

b.     Smolka A, Weinstein WM. Immunoassay of pig and human gastric proton pump. Gastroenterology. 1986 Mar;90(3):532-9. PubMed PMID: 2417911.

c.     Smolka A, Swiger KM. Site-directed antibodies as topographical probes of the gastric H,K-ATPase alpha-subunit. Biochim Biophys Acta. 1992 Jul 8;1108(1):75-85. PubMed PMID: 1643082.

d.     Smolka AJ, Larsen KA, Schweinfest CW, Hammond CE. H,K-ATPase alpha subunit C-terminal membrane topology: epitope tags in the insect cell expression system. Biochem J. 1999 Jun 15;340 ( Pt 3):601-11. PubMed PMID: 10359643; PubMed Central PMCID: PMC1220290.

Solution at 2.8Å resolution of the first P-type ATPase structure in 2000 by X-ray crystallography de-emphasized the value of classical membrane protein structure-function studies based on epitope mapping. Seeking new challenges, and intrigued by H. pylori’s ability to withstand the acidic assault launched by gastric H,K-ATPase, I proposed and tested the novel hypothesis that amongst its defenses the bacterium deploys targeted inhibition of cellular H,K-ATPase gene expression. My work in this field, cited here, remains the most comprehensive molecular account to date of how H. pylori accomplishes this feat. H. pylori produces virulence factors that hijack host cell signaling pathways to mobilize NF-kB p50 homodimers to the nucleus where they bind to the HKa gene promoter, repressing transcription. These factors also up-regulate parietal cell miR-1289, which restricts translation of HKa mRNA.

a.     Göõz M, Hammond CE, Larsen K, Mukhin YV, Smolka AJ. Inhibition of human gastric H(+)-K(+)-ATPase alpha-subunit gene expression by Helicobacter pylori. Am J Physiol Gastrointest Liver Physiol. 2000 Jun;278(6):G981-91. PubMed PMID: 10859229.

b.     Saha A, Hammond CE, Trojanowska M, Smolka AJ. Helicobacter pylori-induced H,K-ATPase alpha-subunit gene repression is mediated by NF-kappaB p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G795-807. PubMed PMID: 18202112.

c.     Mueller D, Tegtmeyer N, Brandt S, Yamaoka Y, De Poire E, Sgouras D, Wessler S, Torres J, Smolka A, Backert S. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest. 2012 Apr;122(4):1553-66. PubMed PMID: 22378042; PubMed Central PMCID: PMC3314471.

d.     Smolka AJ, Backert S. How Helicobacter pylori infection controls gastric acid secretion. J Gastroenterol. 2012 Jun;47(6):609-18. PubMed PMID: 22565637.

My discovery that H. pylori infection of gastrointestinal cells in culture led to repression of transfected HKa promoter-reporter constructs within a few hours of infection helped explain the onset of transient hypochlorhydria. This characteristic of human H. pylori infections is not marked by morphological damage to parietal cells. Since IL-1b is a potent acid inhibitor, we investigated whether H. pylori’s acid inhibition was mediated by IL-1 b. Concurrently we investigated mechanisms whereby H. pylori is able to breach the gastric epithelial barrier. In both cases we provided the first evidence for IL-1 b interaction with HKa gene transcription and its role in activation of matrix metalloproteinases. These findings provided mechanistic underpinnings for the role of host IL-1 b polymorphisms in pathophysiology of H. pylori infection, and identified yet another mechanism of H. pylori-induced increase in mucosal permeability.

a.     Göõz M, Göõz P, Smolka AJ. Epithelial and bacterial metalloproteinases and their inhibitors in H. pylori infection of human gastric cells. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G823-32. PubMed PMID: 11518695.

b.     Gööz M, Shaker M, Gööz P, Smolka AJ. Interleukin 1beta induces gastric epithelial cell matrix metalloproteinase secretion and activation during Helicobacter pylori infection. Gut. 2003 Sep;52(9):1250-6. PubMed PMID: 12912854; PubMed Central PMCID: PMC1773796.

c.     Saha A, Hammond CE, Gooz M, Smolka AJ. IL-1beta modulation of H,K-ATPase alpha-subunit gene transcription in Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol. 2007 Apr;292(4):G1055-61. PubMed PMID: 17204545.

d.     Saha A, Hammond CE, Gooz M, Smolka AJ. The role of Sp1 in IL-1beta and H. pylori-mediated regulation of H,K-ATPase gene transcription. Am J Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G977-86. PubMed PMID: 18772363; PubMed Central PMCID: PMC2584829.

Over the years, my engagement with mechanisms and repercussions of gastric acid secretion led to contributions in closely related fields, and these are documented in part here. The first citation documents one of several papers addressing expression of H,K-ATPase in relatively ancient species and/or extra-gastric locations. The extraordinary specificity and high affinity of my H,K-ATPase a subunit monoclonal antibody HK 12.18 was finally localized to a carboxy-terminal DMDPSEL heptapeptide in the HKa subunit. (ref. b). My interest in novel therapeutic inhibition of gastric acid secretion is exemplified in ref. c, as is my discovery of miR-1289 and its potential as an alternative to PPI anti-secretory approaches (cited in my Personal Statement above). Finally, my proteomic approach to early detection of esophageal carcinomas, the first of its kind, was inspired by the realization that circulatory perfusion of tumors must populate plasma with protein and/or peptide signatures diagnostic of disease.

a.     Swenson ER, Fine AD, Maren TH, Reale E, Lacy ER, Smolka AJ. Physiological and immunocytochemical evidence for a putative H-K-ATPase in elasmobranch renal acid secretion. Am J Physiol. 1994 Oct;267(4 Pt 2):F639-45. PubMed PMID: 7943360.

b.     Smolka AJ, Larsen KA, Hammond CE. Location of a cytoplasmic epitope for monoclonal antibody HK 12.18 on H,K-ATPase alpha subunit. Biochem Biophys Res Commun. 2000 Jul 14;273(3):942-7. PubMed PMID: 10891352.

c.     Smolka AJ, Goldenring JR, Gupta S, Hammond CE. Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative ML 3000. BMC Gastroenterol. 2004 Feb 10;4:4. PubMed PMID: 15028114; PubMed Central PMCID: PMC368434.

d.     Schwacke J, Millar TP, Hammond CE, Saha A, Hoffman BJ, Romagnuolo J, Hill EG, Smolka AJ. Discrimination of normal and esophageal cancer plasma proteomes by MALDI-TOF mass spectrometry. Dig Dis Sci. 2015 Jun;60(6):1645-54. PubMed PMID: 25577268.

Complete List of Published Work in My Bibliography:
https://www.ncbi.nlm.nih.gov/sites/myncbi/adam.smolka.1/bibliography/45770124/public/?sort=date&direction=ascending