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Roger T Worrell, PhD
Research Assistant Professor
roger.worrell@uc.edu

The research interests of our laboratory are focused on ion absorption and secretion in the intestine in health and disease states. Research efforts follow along four lines based on current projects: (1) Ammonium transport and effects on transport in colon; (2) Capsaicin (the “hot” in pepper) effect on colonic Cl/HCO3 secretion; (3) Regulation of ion transporter polarization and trafficking; and (4) Intestinal ischemia/reperfusion injury. Other specific projects of interest to the student and which relate to the general direction of the laboratory may also be arranged.

Ammonium transport and effects on transport in colon:  Increased levels of blood ammonia can cause brain malfunction, referred to as hyperammonemia induced encephalopathy. Left untreated this condition can become life threatening. Liver disease is often the cause of hyperammonemia, however treatment regimes are targeted to the intestine in an effort to minimize ammonia absorption.  Current treatments may have uncomfortable or severe side effects. The long term goal of this project is to provide improved treatment for hyperammonemia. A number of diseases affecting the gastrointestinal tract are characterized by the dysregulation of ion and fluid transport resulting in diarrhea or constipation. Over the past fifty years a plethora of studies have focused on possible mechanisms and treatments for these abnormalities. Ion transport in the colon has been a target of particular interest. It was recognized early on that ammonium (NH4+) in colonic effluent far exceeded that of systemic NH4+ concentration and that, in cases of liver failure, systemic NH4+ levels could exceed toxic concentrations. Although colonic absorption of NH4+ is widely recognized, the possibility of regulated ammonia (NH3) / NH4+ transport in the colon has received little attention, this despite the fact that such transport does occur in a number of epithelia exposed to a high NH4+ environment. Moreover, the effects of relative high and variable NH4+ in the colonic lumen on the balance ion and fluid transport are poorly understood. Proposed research addresses: (1) The mechanisms of absorptive and secretory transport of NH3 / NH4+ in the colon; (2) The functional role of Rhesus Associated Glycoprotein NH4+ transporters in colon and the impact and regulation of the colonic ammonia secretory vector. This project is funded by NIH R01DK079979 (2008-2013).

Capsaicin effect on colonic Cl-/HCO3- secretion:  Capsaicin is the compound responsible for the “hot” in hot peppers. The principle target tissue for capsaicin action is peripheral neurons. The effects of capsaicin on gut thus far have been attributed to a neuronal action.  In colonic secretory cells, pretreatment with Ca++-agonist results in an attenuation of subsequent cAMP-stimulated Cl- secretion. Since capsaicin treatment results in an increase in intracellular calcium via action on TRPV1 receptors in neurons, this study seeks to determine if capsaicin has a direct effect on epithelial cells. The clinical significance of this study is supported by reports of TRPV1 up-regulation in Inflammatory Bowl Disease and colitis. Furthermore, TRPV1-/- mice have altered susceptibility to various forms of induced-colitis. Particular relevance to human gut function is accentuated by many persons consuming capsaicin. Capsaicin concentrations well within the physiologic effective dose can be achieved, even after intestinal transit, thus exposing the gut mucosa to this potential signaling molecule. The driving hypothesis of this study is that capsaicin-induced internalization of NKCC1 reduces basolateral Cl- loading thereby resulting in a greater fraction of HCO3- secretion driven by basolateral Na+/HCO3- exchanger. This study determines: 1) the impact of capsaicin on forsokolin-induced Cl- secretion using colonic secretory cells, T84. 2) the effect of capsaicin on NKCC1 surface expression. 3) capsaicin functional effects on the relative magnitude of Cl- to HCO3- secretion. Thus, capsaicin may be useful to limit Cl- secretion and possibly promote HCO3- secretion via internalization of NKCC1.  This project is pending application for funding.

Methods used in the laboratory: Short Circuit Current (Isc) and Open Circuit Current (Ioc) to determine transepithelial barrier function and ion transport. Radioisotope tracer flux in epithelia to determine barrier function and ion transport status. Confocal Microscopy to determine ion transporter trafficking. Laser Capture Microdisection and Real Time RT-PCR to determine transporter mRNA levels in GI tissue.  Standard western, immunostaining, and RT-PCR methods are also used. Model systems include Mouse intestine from wild type and transgenic (transporter knockout) mice as well as epithelial cell culture systems.  The lab collaborates with a number of labs at UC as well as at other Universities.  Students rotating in the laboratory would be expected to become proficient in relevant techniques, advance their selected project by appropriate data collection and interpretation, and present their work in progress at Fluxes & Barriers as well as other scientific meetings.

Selected Publications:
  • Roger T Worrell, Lisa Merk and Jeffrey B Matthews (2008) Ammonium transport in the colonic crypt cell line, T84: Role for Rhesus glycoproteins and NKCC1. Am J Physiol Gastrointest Liver Physiol 294, G429-G440.
    View original publication at AJP:GI Online.

  • Jie Xu, Roger T Worrell, Hong C Li, Sharon L Barone, Snezana Petrovic, Hassane Amlal and Manoocher Soleimani (2006) Chloride/bicarbonate exchanger SLC26A7 is localized in endosomes in medullary collecting duct cells and is targeted to the basolateral membrane in hypertonicity and potassium depletion. J Am Soc Nephrol 17, 956-967.
    View original publication at JASN Online.

  • Roger T Worrell, Alison Best, Oscar R Crawford, Jie Xu, Manoocher Soleimani and Jeffrey B Matthews (2005) Apical ammonium inhibition of cAMP-stimulated secretion in T84 cells is bicarbonate dependent. Am J Physiol Gastrointest Liver Physiol 289 G768-G778.
    View original publication at AJP:GI Online.

  • Hong C Li, Peter Szigligeti, Roger T Worrell, Jeffrey B Matthews, Laura Conforti and Manoocher Soleimani (2005) Missense mutations in Na+ : HCO3 cotransporter NBC1 show abnormal trafficking in polarized kidney cells: A basis of proximal renal tubular acidosis. Am J Physiol Renal Physiol 289, F61-F71.
    View original publication at AJP:Renal Online.

  • Roger T Worrell, Jennifer Oghene and Jeffrey B Matthews (2004) Ammonium effects on colonic Cl secretion: anomalous mole fraction behavior. Am J Physiol Gastrointest Liver Physiol 286, G14-G22.
    View original publication at AJP:GI Online.

Publications, Complete List at PubMed


Other Publications, Not Listed in PubMed:

  • Roger T Worrell and Jeffrey B Matthews (2005) Effects of ammonium on ion channels and transporters in secretory cells, in: Cell Volume and Signaling (Advances in Experimental Medicine and Biology, vol 559), Peter K Lauf and Norma C Adragna (Eds), Springer, New York, pp 131-139.
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  • Roger T Worrell, John Cuppoletti and Jeffrey B Matthews (2003) Colonic absorption and secretion, in: Encyclopedia of Gastroenterology, Leonard R Johnson (Ed), Academic Press, San Diego, pp 413-420.


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