Gastroenterology and Hepatology Grants, Awards, & Publications

Areas: Serotonin Transporter (SERT) Host-Microbial Interactions Intestinal Inflammation Epigenetics Aryl hydrocarbon receptor (AhR)

Training Opportunities:

Hands-on experience in cutting cellular and molecular biology techniques, in vitro and in vivo models, organoids and basic knowledge in epithelial transport biology, diarrheal diseases, gut inflammation, serotonin homeostasis.

Grants

RO1 DK098170 01/2014-12/2017 Title: Intestinal 5-HT Transporter: A Novel Therapeutic Target of GI Disorders Role: PI The major goals of this project are to examine the upregulation of serotonin transporter by TGF-beta 1 induced non-SMAD and SMAD induced pathways and their role in counteracting TNF-induced diarrhea.

RO1 DK92441 (Waddah Alrefai, PI) 08/2016-07/2020 Title: Gut-Liver Crosstalk and Bile Acid-Induced Diarrhea Role: Co-I The major goals of this project are to elucidate the mechanisms underlying modulation of FGF-19 in intestinal inflammation.

Awards:

2007 New Investigator Award (Takeda): American Physiological Society

PubMed link for Publications

Lab Video Lin

Overall Focus/Accomplishments: Our group has been involved in elucidating ion transport mechanisms (Na+ and Cl-) in the human intestine with a special emphasis on understanding mechanisms underlying pathophysiology of infectious or inflammatory diarrhea. Our group was the first one to establish techniques for purifying human colonic plasma membranes from organ donor colons and to study the mechanisms of Na+ and Cl- absorption directly in human colonic plasma membranes. We have also been involved in developing better therapeutic modalities for the treatment of diarrheal disorders. We have recently identified several proabsorptive molecules which upregulate intestinal chloride absorption e.g. lysophosphatidic acid, neuropeptide Y and bioactive factors secreted by probiotics. In addition, we have strong interest in inflammatory bowel diseases (IBD) and have been working on amelioration of inflammation by probiotics and peptides e.g. GLP-1 and VIP in nanomedicine formulations. Our studies have highlighted the value of the human intestinal chloride transporter DRA (SLC26A3) as a novel therapeutic target in diarrheal diseases. We have also been able to identify the pathophysiology of enteropathogenic E. coli induced early diarrhea, which appears to occur via internalization of sodium transporter NHE3 and chloride transporter DRA from the cell surface of intestinal epithelial cells in response to EPEC infection. We have also identified the role of monocarboxylate transporter in colonic SCFA absorption via a novel nutrient sensing mechanism. We have also established the role of food additive carrageenan as a potential risk factor in IBD. We have all of the tools and techniques established to assess molecular mechanisms underlying diarrheal diseases utilizing cell culture models, organoids and in in vivo models.

Training Opportunities: I have been involved in training many graduate students, post-docs and junior faculty members in the area of gastrointestinal physiology with special focus on diarrheal diseases and IBD. Many of my trainees are now full time tenured faculty members with their own RO1 or VA Merit Award level funding. I have also served as the director/principal investigator of the T-32 for Department of Medicine, entitled “Molecular Training in Gastroenterology and Hepatology”.

Grant Support:

09/01/16-08/31/21: NIH RO1 (DK92441-05), “Chloride Transporter Downregulation in Infectious Diarrhea.” Principal Investigator

09/28/12-08/31/17: NIH-RO1 (DK54016-11), ” Intestinal Anion Transporters: Function and Regulation” Principal investigator.

07/01/13-06/30/18: NIH-RO1 (DK81858-06). “Probiotics: Potential Therapeutic Roles in Diarrhea” , Principal Investigator.

01/01/17-12/31/20, VA Merit Review, “Mechanisms of NaCl Absorption in the Human Colon”. Principal Investigator

04/01/13-03/31/20. The Department of Veterans Affairs, Senior Research Career Scientist Award, (salary support from the VA for Ph.D. Scientists).

08-01-2016-07-31-2020, NIH-RO1 (DK109709-01).“Gut-Liver Crosstalk in Bile-Acid Induced Diarrhea”. Co-Investigator

Recent Honors/Awards:

University Scholar Award for 2011-2012, University of Illinois, Chicago, IL Keynote Speaker: VISN 18 Research Conference on August 29th and 30th 2013 at Albuquerque, NM Keynote Speaker, “East Meets West: Advances in Gut Microbiome Effects on Pathophysiology of Human Diseases”, March 5-6, 2016, Yangzhou University, Yangzhou, China Takeda Distinguished Scientist Award of American Physiological Society, GI & Liver Section for 2018

RECENT SCIENTIFIC PUBLICATIONS

• 195. Priyamvada S, Anbazhagan AN, Gujral T, Borthakur A, Saksena S, Gill RK, Alrefai WA and Dudeja PK. All-Trans-Retinoic Acid Increases SLC26A3 (DRA) Expression via HNF-1β in intestinal epithelial cells. J. Biol. Chem. 2015 Jun 12;290(24):15066-77. doi: 10.1074/jbc.M114.566356. Epub 2015 Apr 17
• 196. Gill RK, Kumar A, Chatterjee I, Gujral T, Natarajan A, Priyamvada S, Alrefai WA, Dudeja PK and Saksena S. Novel Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1. PLoS One May 8;10(5):e0120447. doi: 10.1371/journal.pone.0120447. eCollection 2015
• 197. Kumar A, Hecht C, Priyamvada S, Anbazhagan AN, Alakkam A, Borthakur A, Alrefai WA, Gill RK and Dudeja PK. Probiotic Bifidobacterium species Stimulate Human SLC26A3 Gene Function and Expression in Intestinal Epithelial Cells. Am J Physiol., Cell Physiol. 2014, Dec15;307(12):C1084-92 Aug 20:ajpcell.00194.2014. doi: 10.1152/ajpcell.00194.2014. [Epub ahead of print]
• 198. Muthusamy S, Malhotra P, Hosameddin M, Dudeja AK, Borthakur S, Saksena S, Gill RK, Dudeja PK and Alrefai WA. N-glycosylation is Essential for Ileal ASBT Function and Protection Against Proteases. Am J Physiol Cell Physiol. 2015 Jun 15;308(12):C964-71. doi: 10.1152/ajpcell.00023.2015. Epub 2015 Apr 8
• 199. Nazir S, Kumar A, Chatterjee I, Anbazhagan AN, Gujral T, Priyamvada S, Saksena S, Alrefai WA, Dudeja PK, Gill RK. Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways. PLoS One. 2015 May 8;10(5):e0120447. doi: 10.1371/journal.pone.0120447. eCollection 2015
• 200. Kumar, A, Alrefai WA, Borthakur A and Dudeja PK. Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells. Amer. J. Physiol. GI & Liver 2015 Oct 1;309(7):G602-7. doi: 10.1152/ajpgi.00186.2015. Epub 2015 Aug 13.PMID: 26272259
• 201. Gujral T, Kumar A, Priyamvada S, Saksena S, Gill RK, Hodges K, Alrefai WA, Hecht GA and Dudeja PK. Mechanisms of DRA recycling in Intestinal Epithelial Cells: Effect of Enteropathogenic E. coli. Am. J. Physiol. Cell Physiol. 2015 Oct 7:ajpcell.00107.2015. doi: 10.1152/ajpcell.00107.2015. [Epub ahead of print] PMID: 26447204
• 202. Anbazhagan AN, Priyamvada, S, Gujral T, Alrefai WA, Dudeja, PK and Borthakur A. A novel anti-inflammatory role of GPR120 in intestinal epithelial cells. Am. J. Physiol. Cell Physiol. 2016 Apr 1;310(7):C612-21. doi: 10.1152/ajpcell.00123.2015. Epub 2016 Jan 20. PMID: 26791484
• 203. Anbazhagan AN, Priyamvada, Alakkam A, Kumar A, Borthakur A, Saksena S, Gill RK, Alrefai WA, Dudeja, PK. Transcriptional Modulation of SLC26A3 (DRA) by Sphingosine-1-Phosphate. Am J Physiol Gastrointest Liver Physiol. 2016 Apr 14:ajpgi.00308.2015. doi: 10.1152/ajpgi.00308.2015. [Epub ahead of print] PMID: 27079615
• 204. Kravtsov DV, Ahsan MK, Kumari, Van Ijzendoorn SCD, Reys-Mugica M, Kumar, A, Gujral T, Dudeja PK, and Ameen NA. Identification of Intestinal Ion Transport Defects in Microvillus Inclusion Disease. Am J Physiol Gastrointest Liver Physiol. 2016 Jul 1;311(1):G142-55. doi: 10.1152/ajpgi.00041.2016. Epub 2016 May 26. PMID: 27229121
• 205. Asghar MN, Priyamvada S, Nyström JH, Anbazhagan AN, Dudeja PK and Toivola DM. Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am J Physiol Gastrointest Liver Physiol. 2016 Apr 28:ajpgi.00354.2015. doi: 10.1152/ajpgi.00354.2015. [Epub ahead of print] PMID: 27125276
• 206. Priyamvada S, Anbazhagan AN, Kumar A, Soni V, Alrefai WA, Gill RK, Dudeja PK and Saksena S. Lactobacillus acidophilus stimulates intestinal P-glycoprotein expression via a c-Fos/c-Jun dependent mechanism in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 11:ajpgi.00210.2015. doi: 10.1152/ajpgi.00210.2015. [Epub ahead of print] PMID: 26867563
• 207. Anbazhagan AN, Thaqi M, Priyamvada, S, Jayawardena D, Kumar, A, Gujral T, Chatterjee I, Mugarza E, Saksena S, Onyuksel H and Dudeja, PK. GLP1 nanomedicine alleviates gut inflammation. Nanomedicine. 2016 Aug 20. pii: S1549-9634(16)30112-5. doi: 10.1016/j.nano.2016.08.004. [Epub ahead of print]
• 208. Kumar A, Natarajan Anbazhagan A, Coffing HP, Chatterjee I, Priyamvada S, Gujral T, Saksena S, Gill RK, Alrefai WA, Borthakur A, Dudeja PK. Lactobacillus acidophilus Counteracts Inhibition of NHE3 and DRA Expression and Alleviates Diarrheal Phenotype in Mice Infected With Citrobacter rodentium. Am J Physiol Gastrointest Liver Physiol. 2016 Sep 15:ajpgi.00173.2016. doi: 10.1152/ajpgi.00173.2016. [Epub ahead of print] PMID: 27634011
• 209. Singhal M, Manzella C, Soni V, Alrefai WA, Saksena S, Hecht GA, Dudeja PK, Gill RK. Role of SHP2 Protein Tyrosine Phosphatase in SERT Inhibition by Enteropathogenic E. coli (EPEC).
• Am J Physiol Gastrointest Liver Physiol. 2017 Feb 16:ajpgi.00011.2017. doi: 10.1152/ajpgi.00011.2017. [Epub ahead of print]
• 210. Anabazhagan AN, Chatterjee I, Priyamvada S, Kumar A, Tyagi S, Saksena S, Alrefai WA, Dudeja PK and Gill RK. Methods to Study Epithelial Transport Protein Function and Expression in Native Intestine and Caco-2 Cells Grown in 3D. JOVE, 2017 (In Press).

Pubmed Link for Publications:

https://www.ncbi.nlm.nih.gov/pubmed/?term=Dudeja+PK

Research Interests: Bile Acid & Cholesterol Absorption

Bile acids and gut-liver axis:

Bile acids are synthesized in the liver and secreted into the intestine where they play an essential role in lipid and cholesterol absorption. The majority of secreted bile acids are reabsorbed in the distal ileum and only about 5% enter the colon under normal conditions. The uptake of bile acids across the luminal membrane of enterocytes occurs via the Apical Sodium-Dependent Bile Acid Transporter (ASBT). The entry of bile acids into the enterocytes stimulates the expression and secretion of the gut-derived Fibroblast Growth Factor 19, FGF19 (FGF15 in rodents) that circulates to the liver where it suppresses the rate-limiting step of bile acid synthesis. Low levels of FGF19/15 result in overproduction of bile acids and an increase in their intestinal concentrations. Also, a decrease in ASBT function and expression leads to overproduction of bile acids and an increase in their intestinal luminal concentrations. In this regard, exposure of colon to high levels of bile acids stimulates electrolyte and water secretion and impairs epithelial barrier function leading to diarrhea. Our laboratory’s main focus is to investigate the cellular pathways involved in the modulation of these critical regulators of bile acid homeostasis, ileal ASBT and FGF19/15, and determine the contribution of their dysregulation to gut-related disorders such inflammatory bowel disorders and irritable bowel syndrome. Our studies also aim to understand the roles of disturbances in ileal ASBT and FGF19/15 in the development of liver diseases and metabolic disorders including diabetes mellitus.

Intestinal cholesterol absorption:

High levels of plasma cholesterol represent a major risk factor for development of cholesterol-related disorders such as atherosclerosis and coronary heart disease. Intestinal cholesterol absorption has been shown to be a major determinant of plasma cholesterol levels. The Niemann Pick Type-C1 Like 1 (NPC1L1) has been identified as essential transport protein responsible for intestinal cholesterol absorption. NPC1L1 was also shown to be the molecular target of ezetimibe. Our studies seek to delineate the regulatory pathways involved in altering NPC1L1 expression under normal physiological conditions and in diseases associated with hypercholesterolemia such as diabetes mellitus. We are currently investigating the modulation of NPC1L1 protein level by proteosomal and lysosomal pathways. Also, our studies are centered on elucidating the epigenetic mechanisms involved in controlling NPC1L1 expression. The main objective of our investigations is to identify novel targets for therapeutic intervention for efficient reduction of cholesterol absorption and hypercholesterolemia.

GRANTS:

Current:

R01DK109709: Alrefai WA (PI) 8/1/16-7/31/2020 NIH/NIDDK Title: “Gut-liver cross talk in bile acid-induced diarrhea”

R01 DK71596: Alrefai WA (PI) 9/1/11-8/31/17 NIH/NIDDK Title:“Regulation of Intestinal Bile Acid Transport”

VA Merit Review: Alrefai WA (PI) 7/1/13-6/30/017 Title: “Mechanisms and Regulation of Intestinal Cholesterol Absorption”

VA Research Career Scientist: Alrefai WA 4/1/15-3/31/2020

R01 DK54016: Dudeja PK (PI); 4/1/13-3/31/18 Alrefai WA (Co-Investigator)NIH/NIDDK Title: “Human Intestinal Anion Exchangers: Function and Regulation”

R01DK81858: Dudeja PK (PI); 7/1/13-6/30/18 Alrefai WA (Co-Investigator) NIH/NIDDK Title“Probiotics: Potential Therapeutic role in Diarrhea”

R01 DK98170: Gill RK (PI); 1/1/14-12/31 Alrefai WA (Co-Investigator) NIH/NIDDK Title: “Intestinal 5-HT Transporter: A Novel Therapeutic Target for GI Disorders”

Recent Publications:

• Malhotra P, Soni V, Anbazhagan AN, Kumar A, Dudeja A, Saksena S, Gill RK, Dudeja PK and Alrefai WA. Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann Pick-C1-like 1 (NPC1L1) Gene Non-Smad Pathways. PLoS One. 2015 May 8; 10(5):e0120447.
• Priyamvada S, Anbazhagan AN, Gujral T, Borthakur A, Saksena S, Gill RK, Alrefai WA, Dudeja PK. All-trans-retinoic Acid Increases SLC26A3 DRA (Down-regulated in Adenoma) Expression in Intestinal Epithelial Cells via HNF-1β. J Biol Chem. 2015 Jun 12; 290 (24): 15066-77.
• Kumar A, Alrefai WA, Borthakur A, Dudeja PK. Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2015 Oct 1; 309 (7): G602-7.
• Muthusamy S, Malhotra P, Hosameddin M, Dudeja A, Borthakur S, Saksena S, Gill RK, Dudeja PK and Alrefai WA. N-glycosylation is essential for Ileal ASBT protein stability and Protection Against Proteases. Am J Physiol Cell Physiol. 2015 Jun 15; 308 (12): C964-71.
• Gujral T, Kumar A, Priyamvada S, Saksena S, Gill RK, Hodges K, Alrefai WA, Hecht GA, and Dudeja PK. Mechanisms of DRA recycling in Intestinal Epithelial Cells: Effect of Enteropathogenic E. coli. Am J Physiol Cell Physiol. 2015 Dec 15;309(12):C835-46.
• Anbazhagan AN, Priyamvada S, Gujral T, Bhattacharyya S, Alrefai WA, Dudeja PK, Borthakur A. A Novel Anti-inflammatory Role of GPR120 in Intestinal Epithelial Cells. Am J Physiol Cell Physiol. 2016 Jan 20:ajpcell.00123.2015. [Epub ahead of print]
• Priyamvada S, Anbazhagan AN, Kumar A, Soni V, Alrefai WA, Gill RK, Dudeja PK, Saksena S. Lactobacillus acidophilus Stimulates Intestinal P-glycoprotein Expression via a c-Fos/c-Jun Dependent Mechanism in Intestinal Epithelial Cells. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 11:ajpgi.00210.2015. [Epub ahead of print]
• Anbazhagan AN, Priyamvada S, Alakkam A, Kumar A, Borthakur A, Saksena S, Gill RK, Alrefai WA, Dudeja PK. Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate. Am J Physiol Gastrointest Liver Physiol. 2016 Jun 1; 310(11): G1028-35.

Pubmed Link

Research interests:
Our primary research interests focus on the contribution of inflammation and fibrosis on pancreatic cancer through contributions from certain cell signaling cascades including Kras, AKT/PI3K, TGFbeta, and PEDF (Pigment Epithelium-Derived Factor). The basis of our work revolves around the design, generation, and employment of mouse models of pancreatic cancer in order to establish: (1) a means of early detection, (2) improved understanding of disease development and causative events, and (3) chemopreventive and/or therapeutic strategies. To be more clinically relevant, our group utilizes pancreatic cancer cells and tissue from normal and cancer human sources to explore similar events involved in human pancreatic carcinogenesis and correlate these findings with those in mice. We have begun to extend this approach into colon cancer as well. Our research projects including using these systems to examine the effects of increased exposure to omega-3 and omega-6 fatty acids and their link to AKT at the molecular level and advancement of inflammation and proliferation at the cellular level. This includes a longitudinal study using MRI to follow lesion development and other disease parameters, which may serve as an early detection modality with clinical application. We are also investigating the role of altered TGFbeta signaling in the tumor microenvironment (TME; primarily in the stromal and hematopoietic compartments) during the development of early and more advanced stages of pancreatic cancer. Likewise, we are interested in how the loss of PEDF in pancreas (both the epithelium and TME) affects adipose formation, inflammation, and fibrosis as it contributes to disease progression. Our ultimate goal is to define novel pathways and exploit these systems for earlier detection and treatment.

We are convinced that these types of advancements are just around the corner, and we believe our work, along with those from our esteemed colleagues, will eventually achieve these goals. In the end, we want our work to reflect in longer life with better quality for those at risk for or with pancreatic cancer.

Current Support

1R01CA161283-01A1 (Grippo) 07/23/12 – 07/22/17 National Institutes of Health (NIH/NCI) Title: N-3 Fatty Acid-Induced Akt Suppression: Chemoprevention for Pancreatic Neoplasia The main goal of this study is to establish the predominant means with which w-3 fatty acids oppose the development of cancer by suppressing cell growth and survival while promoting cell death.

1R01CA186885 (H.G. Munshi) 09/15/14 – 08/31/17 Title: Targeting BET Bromodomain in Pancreatic Cancer The main goal of this project is to determine how BET proteins mediate chemo-resistance and contribute to fibrosis in vivo. Role: Co-Investigator

1P01CA163200-01A1 (Eibl) 08/01/12 – 07/31/17 National Institutes of Health (NIH/NCI) Title: Targeting Diet-Induced Promotion of Kras-Initiated Pancreatic Adenocarcinoma The overall goal of this program project is to identify mechanisms influenced by dietary compounds that promote mutant Kras-induced pancreatic carcinogenesis and target them for inhibition, with an emphasis on autophagy and mitochondrial dysfunction related to tumorigenesis.

Recent Publications:

• Gounaris E, Heiferman MJ, Heiferman JR, Shrivastav M, Vitello D, Blatner NR, Knab LM, Phillips JD, Cheon EC, Grippo PJ, Khazaie K, Munshi HG, Bentrem DJ. Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS One. 2015 Mar 6;10(3):e0121402
• Xu S, Chheda C, Ouhaddi Y, Benhaddou H, Bourhim M, Grippo PJ, Principe DR, Mascariñas E, DeCant B, Tsukamoto H, Pandol SJ, Edderkaoui M. Characterization of Mouse Models of Early Pancreatic Lesions Induced by Alcohol and Chronic Pancreatitis. Pancreas. 2015 Aug;44(6):882-7.
• Bauer J, Ozden O, Akagi N, Carroll T, Principe DR, Staudacher JJ, Spehlmann ME, Eckmann L, Grippo PJ, Jung B. Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer. Mol Cancer. 2015 Oct 24;14:182.
• Edderkaoui M, Xu S, Chheda C, nami D, Pinkerton KE, Pandol SJ Morvaridi S, Hu RW, Grippo PJ, Mascariñas WE, Principe DR, Knudsen B, Xue J, Habtezion A, Uyemi HDAC Mediates Smoking-Induced Pancreatic Cancer Oncotarget 2016 Feb 16;7(7):7747-60.
• Principe DR, DeCant B, Mascariñas WE, Wayne EA, Diaz AM, Akagi N, Hwang R, Pasche B, Dawson DW, Fang D, Bentrem DJ, Munshi HG, Jung B, Grippo PJ TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Research 2016 May 1;76(9):2525-39.
• Principe DR, DeCant B, Diaz AM, Mangan RJ, Wayne EA, Jung B, Hwang R, Lowy A, Sreekumar BK, Chung C, Bentrem DJ, Munshi HG, Bishehsari F, and Grippo PJ PEDF Inhibits Pancreatic Tumorigenesis by Attenuating the Fibro-Inflammatory Reaction Oncotarget 2016 May 10;7(19):28218-34.
• Ebine K, Chow CR, DeCant BT, Hattaway HZ, Grippo PJ, Kumar K, Munshi HG. Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia Sci Rep. 2016 Jul 1;6:29133.
• Principe DR, DeCant B, Vitello D, Mangan RJ, Wayne EA, Mascariñas WE, Diaz AM, Bauer-Segura J, McKinney RD, Khashayarsha K, Pasche B, Dawson, DW, Munshi HG, Jung B, Grippo PJ Loss of TGFβ Signaling Promotes Colon Cancer Progression and Tumor-Associated Inflammation.Oncotarget 2016 Jun 4 Epub ahead of print.
• Azevedo-Pouly AC, Sutaria DS, Jiang J, Elgamal OA, Amari F, Allard D, Grippo PJ, Coppola V, Schmittgen TD. miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal. Funct Integr Genomics. 2016 Aug 19. Epub ahead of print.
• Gong J, Belinsky G, Sagheer U, Zhang X, Grippo PJ, Chung C. Pigment Epithelium-derived Factor (PEDF) Blocks Wnt3a-induced Autophagy in Pancreatic Intraepithelial Neoplasms. J Biol Chem. 2016 Oct 14;291(42):22074-22085.
• Schultz MA, Diaz A, Smite S, DeCant B, McKinney R, and Grippo PJ. Kras-Associated Protein Oxidation in Pancreatic Neoplasia and Cancer (invited second submission to Oncotarget 018383).

ACHIEVEMENTS:

Outstanding Performance in Problem Based Learning, Northwestern University 2011-2012.

Co-Chairman, “Mouse Models of Human Cancer” Minisymposium 2012 AACR Annual Meeting.

Moderator, “Obesity, Dietary Fat, and Pancreatic Diseases” Translational Symposium, 2014 DDW

Moderator, Pancreatic Cancer Abs. Session, 2015 Annual Meeting of the American Pancreatic Association

Overall Focus/Accomplishments: For the past several years, I have been involved in elucidating mechanisms underlying regulation of intestinal ion transport processes and their implications in the pathophysiology of diarrheal diseases associated with inflammation or enteric infections. Our findings over the last several years have yielded important data demonstrating the importance of DRA as a novel therapeutic target for diarrhea. Further, I developed a keen interest in studying another physiologically important intestinal transporter, P-glycoprotein (Pgp)/MDR1) that is well known to play a direct role in the pathogenesis of IBD. We focused our efforts on investigating the molecular and cellular mechanisms involved in regulating intestinal P-glycoprotein under both physiological and pathophysiological conditions. Our work has provided novel insights into the role of proteasomal degradation pathway in the regulation of Pgp function and expression in response to pro-inflammatory mediator, Angiotensin II. These studies are of critical relevance to IBD, since several studies have shown that dysregulation of intestinal homeostasis in IBD, may be triggered by decreased Pgp function and expression. Also, our findings on the up-regulation of Pgp by probiotics and growth factors involving c-Fos/c-Jun transcription factors & Erk1/2 MAP kinase could provide the basis for new and more efficacious therapeutic modalities for the treatment of IBD, where Pgp function and expression are significantly impaired. We are currently involved in delineating the mechanisms underlying epigenetic regulation of NHE3 and define important mechanistic link between alterations in DNA methylation/histone modifications of NHE3 gene and diarrhea associated with IBD. These studies represent a logical extension to our previous and ongoing studies, which suggest NHE3 as another novel and emerging therapeutic target for diarrhea associated with inflammation and will be helpful in developing potential therapeutic targets to counteract the suppression of NHE3 and alleviate diarrhea.

Research Interests

• P-glycoprotein/MDR1 & Intestinal Inflammation
• P-glycoprotein/MDR1 & Intestinal Homeostasis
• Na+/H+ Exchanger-3 (NHE3)/Cl-/HCO3- Exchangers & Intestinal Electrolyte Absorption
• Epigenetic Regulation of NHE3 & Pathophysiology of Diarrhea

Grant Support:

VA Merit Award 04/2015-03/2019 Title: Epigenetic Regulation of Intestinal NA+/H+ Exchanger-3 Role: PI The overall goal of this project is to elucidate the molecular mechanisms involved in the epigenetic regulation of intestinal NHE3.

RO1-DK92441 09/2016-03/2021 Title: Chloride Transporter Downregulation in Infectious Diarrhea Role: Co-I The overall goal of this project is to elucidate the molecular mechanisms involved in the regulation of intestinal chloride transporter (DRA) in infectious diarrhea.

Honors/Awards

2012-2015 Exploratory/Developmental Research Grant Award (R21) National Institutes of Health (NIDDK)

2008-2010 Mentored Career Development Award (CDA) Crohn’s and Colitis Foundation of America (CCFA)

Original Scientific Publications:

Singhal M, Manzella C, Soni V, Alrefai WA, Saksena S, Hecht GA, Dudeja PK, Gill RK. Role of SHP2 Protein Tyrosine Phosphatase in SERT Inhibition by Enteropathogenic E. coli (EPEC).Am J Physiol Gastrointest Liver Physiol. 2017 Feb 16:ajpgi.00011.2017. doi: 10.1152/ajpgi.00011.2017.

Anbazhagan AN, Chatterjee I, Priyamvada S, Kumar A, Tyagi S, Saksena S, Alrefai WA, Dudeja PK, Gill RK. Methods to study epithelial transport protein function and expression in native intestine and Caco-2 cells grown in 3 dimensions. JOVE, 2016 (In Press)

Kumar A, Anbazhagan AN, Coffing H, Chatterjee I, Priyamvada S, Gujral T, Saksena S, Gill RK, Alrefai WA, Borthakur A, Dudeja PK. Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. Am J Physiol Gastrointest Liver Physiol. 2016 Nov 1;311(5):G817-G826. doi: 10.1152/ajpgi.00173.2016.

Anbazhagan AN, Thaqi M, Priyamvada S, Jayawardena D, Kumar A, Gujral T, Chatterjee I, Mugarza E, Saksena S, Onyuksel H, Dudeja PK. GLP-1 nanomedicine alleviates gut inflammation. Nanomedicine, 2016Aug 20;13(2):659-665. doi: 10.1016/j.nano.2016.08.004.

Anbazhagan AN, Priyamvada S, Alakkam A, Kumar A, Borthakur A, Saksena S, Gill RK, Alrefai WA and Dudeja PK. Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate. Am J Physiol Gastrointest Liver Physiol. 2016, Jun 1; 310(11): G1028-35. Epub 2016 Apr 14.

Priyamvada S, Anbazhagan AN, Kumar A, Soni V, Alakkam A, Alrefai WA, Gill RK, Dudeja PK and Saksena S*. Lactobacillus acidophilus Stimulates Intestinal P-glycoprotein Expression via a c-Fos/c-Jun Dependent Mechanism in Intestinal Epithelial Cells. Am J Physiol Gastrointest Liver Physiol. 2015, Apr 15; 310(8): G599-608. Epub 2016 Feb 11.

Gujral T, Kumar A, Priyamvada S, Saksena S, Gill RK, Hodges K, Alrefai WA, Hecht GA, Dudeja PK. Mechanisms of DRA Recycling in Intestinal Epithelial Cells: Effect of Enteropathogenic E. coli. Am J Physiol Cell Physiol. 2015, Dec 15; 309(12): C835-46. Epub 2015 Oct 7

Nazir S, Kumar A, Chatterjee I, Anbazhagan AN, Gujral T, Priyamvada S, Saksena S, Alrefai WA, Dudeja PK, Gill RK. Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways. PLoS One. 2015, May 8; 10(5): e0120447. eCollection 2015

Priyamvada S, Anbazhagan AN, Gujral T, Borthakur A, Saksena S, Gill RK, Alrefai WA, Dudeja PK. All-trans-retinoic Acid Increases SLC26A3 DRA (Down-regulated in Adenoma) Expression in Intestinal Epithelial Cells via HNF-1β. J Biol. Chem. 2015, 290(24): 15066-77. Epub 2015 Apr 17

Muthusamy S, Malhotra P, Hosameddin M, Dudeja AK, Borthakur S, Saksena S, Gill RK, Dudeja PK Alrefai WA. N-glycosylation is essential for ileal ASBT function and protection against proteases. Am J Physiol Cell Physiol. 2015, 308(12): C964-71. Epub 2015 Apr 8