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Research Interest

Adaptation to the changes in intracellular oxygen levels is a challenge to the tissues particularly liver, a hub of all metabolic responses. A highly conserved transcription factor, hypoxia-inducible transcription factor (HIF) orchestrates the adaptive response to low oxygen levels (hypoxia). However, chronic activation of HIF is shown to be detrimental and can lead to the numerous pathologies including fatty liver. The upstream pathways and signaling cues that are involved in the activation of HIF, independent of intracellular oxygen levels, remain unknown. Furthermore, the HIF-driven pathophysiological mechanisms that are involved in the progression of fatty liver to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains to be elucidated.  Obesity is a chronic inflammatory disease which is associated with activation of HIF signaling in various tissues. Intestine, once seen as an organ with sole purpose of nutrient absorption, is now being revisited on its role in obesity associated co-morbidities through extensive research on gut microbiota. However, very little is known on the contribution of intestinal barrier function in the pathogenesis of NASH and HCC. Our research interest is to (i) investigate the mechanism by which physiological and pathological cues activate the hypoxic response in the liver, (ii) determine the role of hypoxia-mediated metabolic adaptation in fatty liver disease and liver cancer, (iii) determine the hypoxia-dependent and independent mechanisms of intestinal barrier dysfunction in the pathogenesis of NASH, (iv) identify isoform specificity and therapeutic potential of HIFs in metabolic diseases and cancer.

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Team

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Sadeesh K. Ramakrishnan PhD

Principal Investigator

Education:

2004 BVSc and AH (DVM), Pondicherry University, India

2006 MVSc, Indian Veterinary Research Institute, India

2012 PhD, University of Toledo, OH

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Position:

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2012 Postdoctoral Fellowship, University of Michigan, MI

2018 Assistant Professor of Medicine, University of Pittsburgh, PA

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Anil Kumar Pasupulati PhD

Visiting Scholar

Education​

2002 M.Sc. Andhra University, Visakhapatnam, India

2008 Ph.D. Osmania University, Hyderabad, India

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Position

2014- Assistant Professor, University of Hyderabad, Hyderabad, India

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Dhanunjay Mukhi MS

Research Assistant

Education
2013 M.Sc. University of Hyderabad, Hyderabad, India
2015-present PhD University of Hyderabad, Hyderabad, India

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Akeem Williams

Undergraduate Lab Assistant

Education
2016-2020 B.S Neuroscience

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Joseph Michael Capooci

Undergraduate Student Researcher

Education
2015-2019 B.S Biology

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Julianna Latini

Undergraduate Student Researcher

Education
2017-21: B.S. Microbiology

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PUBLICATIONS

PEER REVIEWED PUBLICATIONS

  1. Bechtel JM, Wittenschlaeger T, Dwyer T, Song J, Arunachalam S, Ramakrishnan SK, Shepard S, Fedorov A. Genomic Mid-Range Inhomogeneity Correlates with an Abundance of RNA Secondary Structures. BMC Genomics2008 Jun 12;9:284.

  2. Hinds TD Jr, Ramakrishnan S, Cash HA, Stechschulte LA, Heinrich G, Najjar SM, Sanchez ER. Discovery of Glucocorticoid Receptor-Beta in Mice with a Role in Metabolism.Mol Endocrinol2010 Sep; 24(9):1715-27.

  3. Bowman TA*, Ramakrishnan SK*, Kaw M, Lee SJ, Patel PR, Golla VK, Bourey RE, Haram PM, Koch LG, Britton SL, Wisløff U, Lee AD, Najjar SM. Caloric Restriction Reverses Hepatic Insulin Resistance and Steatosis in Rats with Low Aerobic Capacity.Endocrinology2010 Nov;151(11):5157-64. * equal contribution.

  4. Wuescher L, Angevine K, Hinds T, Ramakrishnan S, Najjar SM, Mensah-Osman EJ.Insulin Regulates Menin Expression, Cytoplasmic Localization, and Interaction with FOXO1.Am J Physiol Endocrinol Metab2011 Sep; 301(3):E474-83. 

  5. Patel PR, Ramakrishnan SK, Kaw MK, Raphael CK, Ghosh S, Marino JS, Heinrich G, Lee SJ, Bourey RE, Hill JW, Jung DY, Morgan DA, Kim JK, Rahmouni SK, Najjar SM. Increased Metabolic Rate and Insulin Sensitivity in Male Mice Lacking the Carcinoembryonic Antigen-Related Cell Adhesion Molecule 2. Diabetologia2012 Mar; 55(3): 763-72.

  6. Najjar SM, Ledford KJ, Abdallah SL,Paus A, Russo L, Kaw MK, Ramakrishnan S, Muturi HT, Raphael CK,Lester SG, Heinrich G, Pierre SV, Benndorf R, Kleff V, Jaffa AA,Levy E, Vazquez G, Goldberg IJ,Beauchemin N, Scalia R, and Ergün S. Ceacam1 Null Deletion Causes Vascular Alterations in Large Vessels. Am J Physiol Endocrinol Metab2013 Aug 15;305(4):E519-29. 

  7. Xue X, Ramakrishnan S, Taylor M, and Shah YM. Endothelial PAS Domain Protein 1 Activates the Epithelial-Elicited Pro-Inflammatory Response to Promote Colitis in Mice. Gastroenterology2013 Oct; 145(4):831-41. 

  8. Anderson ER, Taylor M, Xue X, Ramakrishnan SK, Martin A, Xie L, Bredell BX, Gardenghi S, Rivella S, and Shah YM. Intestinal HIF2α Promotes Tissue-Iron Accumulation in Disorders of Iron Overload with Anemia. Proc Natl Acad Sci U S A2013 Dec 10;110(50): E4922-30. 

  9. Ramakrishnan SK, Taylor M, Qu A, Ahn SH, Suresh MV, Raghavendran K, Gonzalez FJ, and Shah YM. Loss of Von Hippel-Lindau (VHL) Increases Systemic Cholesterol Level Through Targeting HIF-2α and Regulation of Bile Acid Homeostasis. Mol Cell Biol2014 Apr; 34(7): 1208-20. 

  10. Xue X*, Ramakrishnan SK* and Shah YM. Activation of HIF-1α does not Increase Intestinal Tumorigenesis. Am J Physiol Gastrointest Liver Physiol 2014 Jul 15;307(2):G187-95. *equal contribution.

  11. Xie L, Xue X, Taylor M, RamakrishnanSK, Nagaoka K, Hao C, Gonzalez FJ and Shah YM. HIF/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin Leading to Hypoxia-induced Inflammation. Mol Cell Biol2014 Aug;34(16):3013-23. 

  12. Holden VI, Lenio S, Kuick R, Ramakrishnan SK, Shah YM, Bachman MA.Bacterial Siderophores that Evade or Overwhelm Lipocalin 2 Induce HIF-1α and Pro-Inflammatory Cytokine Secretion in Cultured Respiratory Epithelial Cells. Infect and Immun2014 Sep;82(9):3826-36.

  13. Madathilparambil SV, Ramakrishnan SK, Thomas B, David MA, Bi Y,Nicholas T, Anderson ER, Shah YM , and RaghavendranK. Activation of Hypoxia Inducible Factor (HIF)-1 in Type 2 Alveolar Epithelial Cell is a Major Driver of Acute Inflammation following LC. Crit Care Med2014 Oct;42(10):e642-53. 

  14. Liu J*, Ramakrishnan SK*, Khuder SS*, Kaw MK*, Muturi MT, Lester SG, Lee SJ, Fedorova LV, Kim AJ, Mohamed IE, Gatto-Weis C, Eisenmann KM, Conran PB, Najjar SM. High-calorie Diet Exacerbates Prostate Peoplasia in Mice with Haploinsufficiency of Pten Tumor Suppressor Gene. Mol Metab2015 Jan 2; 4(3): 186-98. * equal contribution.

  15. Hu B, Guo Y, Garbacz WG, Jiang M, Xu M, Huang H, Tsung A, Billiar TR, Ramakrishnan SK, Shah Y, Lam KSL, Huang M, and Xie W. Fatty acid Binding Protein-4 (FABP4) is a Hypoxia Inducible Gene that Sensitizes Mice to Liver Ischemia/Re-perfusion Injury.J Hepatol2015. Oct;63(4):855-62.

  16. Ramakrishnan SK, Anderson ER, Martin A, Centofanti B, and Shah YM. Maternal Intestinal HIF-2a is Necessary for Sensing Iron Demands of Lactation in Mice. Proc Natl Acad Sci USA 2015 Jul 14;112(28):E3738-47. ** Received Cozzarelli Prize from PNAS for its scientific excellence and originality**.

  17. Al-Share QY, DeAngelis AM, Lester SG, Bowman TA, Ramakrishnan SK, Abdallah SL, Russo L, Patel PR, Kaw MK, Raphael CK, Kim AJ, Heinrich G, Lee AD, Kim JK, Kulkarni RN, Philbrick WM, Najjar SM. Forced Hepatic Over-expression of CEACAM1 Curtails Diet-induced Insulin Resistance. Diabetes2015 Aug;64(8):2780-90.

  18. Das N, Xie L, Ramakrishnan SK, Campbell A, Rivella S, and Shah YM. Intestine Specific Disruption of HIF-2aImproves Anemia in Sickle Cell Disease. J Biol Chem2015 Sep 25;290(39):23523-7.

  19. Zhang H*, Ramakrishnan SK*, Triner D,Maitra D, GyÅ‘rffy B, Sebolt-Leopold JS, Dame MK, Varani J, Brenner DE, Fearon ER, Omary BM, Shah YM.Tumor-Selective Proteotoxicity of Verteporfin Inhibits Colon Cancer Progression independent of YAP1. Sci Signal2015 Oct 6;8(397):ra98. * equal contribution.

  20. Ghanem SS, Heinrich G, Lester SG, Pfeiffer V, Bhattacharya S, Patel PR, DeAngelis AM, Dai T, Ramakrishnan SK, Smiley ZN, Jung DY, Lee Y, Kitamura T, Ergun S, Kulkarni RN, Kim JK, Giovannucci DR, Najjar SM. Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem2016 Jan 8;291(2):980-8.

  21. Mori H, Yao Y, Learman BS, Kurozumi K, Ishida J, Ramakrishnan SK, Overmyer KA, Xue X,Cawthorn WP,Reid MA, Taylor M, Ning X, Merajver SD, Shah YM, Ormond A. MacDougald. Induction of WNT11 by Hypoxia and Hypoxia-Inducible Factor-1α Regulates Cell Proliferation, Migration and Invasion. Sci Rep.2016 Feb 10;6:21520.

  22. Ramakrishnan SKand Shah YM. Role of Intestinal HIF-2α in Health and Disease. Annu Rev Physiol 2016 Feb 10;78:301-25.

  23. Ro SH, Xue X, Ramakrishnan SK, Jang I, Park HW, Semple IA, Shah YM and Lee JH.Sestrin2 Suppresses Colon Inflammation and Tumor Development in Mice. eLife 2016;5:e12204.

  24. Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy B, Weisz K, Chen Z, Uhler MD, Rui L, Gonzalez FJ, and Shah YM. HIF-2ais an Essential Molecular Brake for Hepatic Glucagon Response Independent of Insulin Signaling.Cell Metab.2016 Mar 8:23(3):505-16.***Featured on the cover of Mar 2016 issue***.

  25. Ramakrishnan SK*, Khuder SS*, Al-Share QY*,Russo L,Abdallah SL, Patel PR, Heinrich G, Mopidevi BR,Shah YM, Sanchez ER and Najjar SM.  PPAR alpha Activation Reduces Hepatic CEACAM1 Expression to regulate Fatty Acid Oxidation during Fasting-refeeding Transition. J Biol Chem.2016 Apr 8;291(15):8121-9. * equal contribution.

  26. Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie L,Cadieux JA, GyÅ‘rffy B, Zhan M, Carter-Su C, Hardiman KM, Dame M,Varani J, Brenner D, Fearon ER and Shah YM.Iron Uptake via DMT1Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis.Cell Metabolism. Sep 2016 13;24(3):447-61.***Featured on the cover on Sep 2016 issue***.

  27. Ramakrishnan SK*, Russo L*, Ghanem SS*, Patel PR, Oyarce AM, Heinrich G, Najjar SM. Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Secretion. J Biol Chem.2016 Nov 11;291(46):23915-23924.* equal contribution.

  28. Ramakrishnan SKand Shah YM. A central role for hypoxia-inducible factor (HIF)-2ain hepatic glucose homeostasis. Nutrition and Healthy Aging. (2017).

  29. McEnerney L, Duncan K, Bang B, Elmasry S, Li M, Miki T, Ramakrishnan S, Shah Y and Saito T. Canonical and Non-canonical Wnt pathways Dual-Modulation of Human Hepatic Zonation. Exp Mol Med. 2017 Dec 15;49(12)e413.

  30.  Xie C, Yagai T, Sun D, Wang Q, Liang X, Jiang C, Li J, Ramakrishnan SK, Xue X, Krausz KW, Liu Y, Shah YM, Jiang C* and Gonzalez FJ*. Activation of intestinal hypoxia-inducible factor 2a during obesity mediates non-alcoholic fatty liver disease. Nat Med.2017 Nov;23(11):1298-1308.

  31. Heather K. Schofield, Min-Jung Park, Sadeesh K. Ramakrishnan, Esther Kim, Jiaqi Shi, M Bishr Omary, Yatrik M. Shah and Marina Pasca di Magliano. Pancreatic HIF2 overexpression results in disrupted morphology resembling human chronic pancreatitis and mucinous cystic neoplasm. CMGH. 2018 5(2): 169-185.e2.

  32. Kim DI, Liao J, Emont MP, Park MJ, Jun H, Ramakrishnan SK, Lin JD, Shah YM, Omary MB, Wu J. An OLTAM system for analysis of brown/beige fat thermogenic activity.Int J Obes (Lond).2018 Apr;42(4):939-945.

  33. Holly Turula, Juliana Bragazzi Cunha, Sadeesh Ramakrishnan, Carol A. Wilke, Mariam B. Gonzalez-Hernandez, Alexandra Pry, Julianne Fava, Jacob Edelman, Yatrik Shah, Blaise Corthesy, Bethany B. Moore, Christiane E. Wobus. Natural Secretory Immunoglobulins Promote Enteric Viral Infections. J of Virology. (2018).

  34. Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic M, Wu J, Nemeth E, Lakhal-Littleton S, Colacino JA, Shah YM. Hepatic hepcidin/intestinal HIF-2a axis maintains iron absorption during iron deficiency and overlaod. J Clin Invest. (2018). In Press. 

  35. Triner D, Davenport SN, Ramakrishnan SK, Ma X, Frieler RA, Greenson JK, Inohara N, Nunez G, Colacino JA, Mortensen RM, Shah YM. Neutrophils Restrict Tumor-Associated Microbiota to Reduce Growth and Invasion of Colon Tumors in Mice.  Gastroenterology (2018). In Press.

  36. Suresh MC, Balaijepalli S, Zhang B, Sing VV, Swamy S, Panicker S, Dolgachev VA, Subramanian C, Ramakrishnan SK, Thomas B, Rao TC, Delano MJ, Machado-Aranda D, Shah Y, Rahavendran K. Hypoxia-Inducible Factor (HIF)-1a promotes inflammation and injury following aspiration-induced lung injury in mice. Shock (2018). In Press.

  37. Sadeesh K. Ramakrishnan*, Huabing Zhang, Xiaoya Ma, Inkyung Jung, Andrew J. Schwartz, Daniel Triner, Samantha N. Devenport, Nupur K. Das, Xiang Xue,  Melody Y. Zeng, Yinling Hu, Richard M. Mortensen, Joel K Greenson, Marilia Cascalho, Christiane E. Wobus, Justin A. Colacino, Gabriel Nunez, Liangyou Rui, and Yatrik M. Shah*. Intestinal non-canonical NFkB signaling shapes the local and systemic immune response. Nature Communications. In Press. *Co-corresponding author.

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Positions available

Postdoc opportunity

A Postdoctoral position is available immediately in the laboratory of Dr. Sadeesh Ramakrishnan in the Division of Endocrinology and Metabolism, Department of Medicine at the University of Pittsburgh. The research interests of Ramakrishnan laboratory are to determine the conserved role of hypoxia signaling in metabolic elasticity as an impetus to design effective therapies to treat metabolic diseases and their complications. The candidate’s research focus involves determining the role of hepatic hypoxia signaling in Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma. The candidate is expected to be a good team player in our rich academic and scientific environment. Candidates will have the opportunity to work with novel animal models and cutting-edge technology. 

            A Ph.D. in Biochemistry, Cell Biology, Molecular Biology, Physiology or a related field is required. Candidate must have good writing and verbal communication skills, along with experience in cell and molecular biology techniques. Experience in working with animal models is preferred. Please send your CV, a cover letter detailing your research experience and interests, and contact details of references to ramaks@pitt.edu.

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