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