This is a 5-year training plan for a mentored physician scientist in Gastroenterology and Hepatology. The Principal Investigator is a junior faculty member in the Division of Gastroenterology and Hepatology at University of Maryland School of Medicine (UMSOM). Drs. Thomas Pallone and Jean-Pierre Raufman will co-mentor the Pi's scientific training. Dr. Pallone (Professor, Departments of Medicine and Physiology) is a renowned leader in microcirculation. Dr. Raufman (Chief, Division of Gastroenterology and Hepatology) has expertise in bile acid signaling. An Advisory Committee of established scientists/mentors will provide scientific and career guidance. The UMSOM provides an ideal training environment for the Pi's academic career development. The combination of mentoring, didactic coursework, unwavering institutional support and commitment will maximize the Pi's ability to launch a productive scientific career. The proposed study focuses on elucidating the mechanisms of vascular dysfunction in cirrhosis. The preliminary data indicates that (i) conjugated bile acids (BA) induce vasodilation in rodent aortae;(ii) BA-mediated vasodilation is endothelium-dependent and nitric oxide (NO)-mediated;(iii) M3 muscarinic receptor inhibition and ablation attenuates BA- and acetylcholine-mediated vasodilation. Our central hypothesis is that cholinergic stimulation of vascular endothelial cells mediates vascular dysfunction and systemic vasodilation in cirrhosis.
The Specific Aims are (1) To define the role of M3R-dependent signaling in bile acid-mediated vasodilation;(2) To establish that bile acid-mediated changes in small mesenteric arterial tone mimic changes in aortic vascular tone;(3) To determine the mechanism whereby M3R contributes to vascular dysfunction in a mouse model of cirrhosis. Portal hypertension is a major cause of morbidity and mortality in advanced liver disease and vascular dysfunction contributes significantly to the progression of portal hypertension in this setting. The proposed complementary in vitro and in vivo approaches will help (a) determine the importance of cholinergic stimulation in the development of NO-mediated stress in EC, (b) elucidate molecular mechanisms of BA- mediated vasodilation and (c) determine the impact of M3R knockdown on vascular dysfunction in the animal model of experimental cirrhosis. This line of investigation will fill critical gaps in understanding the mechanisms of vascular dysfunction in cirrhosis and identify molecules for therapeutic targeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK081479-05
Application #
8293282
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (M3))
Program Officer
Podskalny, Judith M,
Project Start
2008-07-28
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$136,946
Indirect Cost
$10,144
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cheng, Kunrong; Xie, Guofeng; Khurana, Sandeep et al. (2014) Divergent effects of muscarinic receptor subtype gene ablation on murine colon tumorigenesis reveals association of M3R and zinc finger protein 277 expression in colon neoplasia. Mol Cancer 13:77
Vivian, Diana; Cheng, Kunrong; Khurana, Sandeep et al. (2014) In vivo performance of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transport. Mol Pharm 11:1575-82
Khurana, Sandeep; Raina, Hema; Pappas, Valeria et al. (2012) Effects of deoxycholylglycine, a conjugated secondary bile acid, on myogenic tone and agonist-induced contraction in rat resistance arteries. PLoS One 7:e32006
Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L (2011) Bile acids regulate cardiovascular function. Clin Transl Sci 4:210-8
Raufman, Jean-Pierre; Xu, Su; Cheng, Kunrong et al. (2011) In vivo magnetic resonance imaging to detect biliary excretion of 19F-labeled drug in mice. Drug Metab Dispos 39:736-9
Raufman, Jean-Pierre; Shant, Jasleen; Xie, Guofeng et al. (2011) Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice. Carcinogenesis 32:1396-402
Raufman, Jean-Pierre; Cheng, Kunrong; Saxena, Neeraj et al. (2011) Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells. Biochem Biophys Res Commun 415:319-24
Khurana, Sandeep; Shah, Nirish; Cheng, Kunrong et al. (2010) Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury. J Pharmacol Exp Ther 333:639-49
Khurana, Sandeep; Simcox, Thomas; Twaddell, William et al. (2010) Dialysis reduces portal pressure in patients with chronic hepatitis C. Artif Organs 34:570-9
Shah, Nirish; Khurana, Sandeep; Cheng, Kunrong et al. (2009) Muscarinic receptors and ligands in cancer. Am J Physiol Cell Physiol 296:C221-32