Faculty, Department of Molecular Therapeutics
Faculty, Graduate Program
One third of the US population is obese and at risk of several age related diseases such as, diabetes, cardiovascular disease and neurodegeneration. Current anti-obesity drugs target food intake or absorption and have toxic side effects like psychiatric and digestive problems. My current research focus is directed to unraveling novel pathways as potential drug targets for improving peripheral fatty acid metabolism with lesser side effects—without compromising consumption!
One such target is IP7 (diphosphoinositol pentakisphosphate). IP7 is highly energetic inositol pyrophosphate which rapidly turns over in cells. IP7 exerts its biological effects by binding or pyrophosphorylating its protein targets. The most characterized form of IP7 is generated by Inositol hexakisphosphate kinases of which IP6K1 is the major isoform. IP6K1 knockout mice are protected against insulin resistance and weight gain caused by either high fat diet treatment or age. Thus, pharmacologic inhibition of IP6K1 or targeting IP6K1 interaction with certain proteins may have therapeutic potential in age associated metabolic complications. My laboratory is currently focusing on the following areas:
To investigate the molecular mechanism by which IP6K1 regulates lipid metabolism: Lipid mass and metabolic profiles in IP6K1 knockout mice indicate that IP6K1/IP7 may directly regulate lipid homeostasis. Employing biochemical and Mass spectrometric experiments we discovered that IP6K1 binds and regulates key proteins in lipid metabolism. We are investigating how IP6K1’s interactions with these proteins modulate their function in vitro and fatty acid metabolism in vivo.
Pharmacologic inhibition of IP6K by the commercially available inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] blocks lipid accumulation in NIH3T3-L1 cells. We will be testing in vivo effects of TNP in energy metabolism in diabetic and obese mouse models. In collaboration with leading chemists, my laboratory investigates functional efficacy of various IP6K inhibitors in vitro and in vivo.
To unravel complexities of signal transduction pathways: The goal of my laboratory is to employ pharmacologic and genetic screening approaches to discover novel compounds and proteins which regulate key signaling processes. Functional significance of these proteins/molecules will enhance our current biological understanding of aging and age related diseases and thus may lead to targets with therapeutic potential.
B.Sc., Zoology, The University of Burdwan, 1995
M.Sc., Zoology, The University of Burdwan, 1997
Ph.D., Biochemistry, Indian Institute of Chemical Biology/Jadavpur University, 2005
Research Instructor: Johns Hopkins Medical Institute, Baltimore, MD, 2009-2012.
Research Associate: Johns Hopkins Medical Institute, Baltimore, MD, 2008-2009.
Postdoctoral Fellow: Johns Hopkins Medical Institute, Baltimore, MD, 2005-2008.
National Research Grant, University Grants Commission (UGC), India: 2000-2004.Ranked 2nd in Graduate Aptitude Test in Engineering (GATE), India: 1999.
Invited speaker, 'Inositol pyrophosphates and obesity' Department of Zoology, The University of Burdwan, India: 2012.
Invited speaker, 'Inositol pyropshosphate signaling in aberrations in obesity and insulin resistance' Department of Zoology, Viswabharati University, India: 2012.
Invited speaker, 'Inositol pyrophosphates and Akt signaling' Lieber Institute for Brain Development, Baltimore, MD: 2012.
Invited speaker, 'IP6K1 mediated regulation of Akt/GSK3 signaling pathway' Johnson and Johnson, La Jolla, CA: 2012.
Invited speaker, 'Implication of IP6K1 regulation of Akt/GSK3 in Cancer' Abbott Laboratories, Chicago, IL: 2011.
Invited speaker, 'Inositol pyrophosphates in insulin homeostasis and weight gain' at Metabolic Signaling Symposium, Department of Biochemistry, University of Utah School of Medicine: 2011.
Invited speaker, 'Targeting IP6K2-HSP90 in cancer' MGI Pharma, Baltimore, MD: 2005.
Member: Sigma Xi, Obesity Society and Society For Neuroscience
Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain., Zhu, Q., Ghoshal, S., Tyagi, R. and Chakraborty, A., Molebular Metabolism, 2016 November 28;6(1); 73-85 Pubmed PMIS:28123939; PMC5220553
Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis. Zhu Q, Ghoshal S, Rodrigues A, Gao S, Asterian A, Kamenecka TM, Barrow JC, Chakraborty A., J Clinical Investigation 2016 Nov 1; 126 (11): 4273-4288. DOI: 10.1172/JCI85510. Epub 2016 Oct 4, PMID:27701146 PMC509689
Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis, Ghoshal, S., Tyagi, R., Zhu, Q., Chakraborty, A., J Biochem Cell Biology, 2016 Sept: 78: 149-55. DOI: 10.1016/j.biocell.2016.06018. Epub Jun 29. PMID 27373682, PMC 5003629
TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway. Ghoshal, S, Zhu, Q., Asteian, A., Lin, H., Xu, H, Ernst, G., Barrow, J.C., Xu, B., Cameron, M.D., Kamenecka, T.M. and Chakraborty, A. Molecular Metabolism 2016 Aug 21; 5(10):903-17. DOI: 10.1016/j.molmet.2016.08.008. eCollection 2016 PMID 27689003 PMC5034689
Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways. Chakraborty A, Latapy C, Xu J, Snyder SH, Beaulieu JM. Mol Psychiatry 2013. doi: 10.1038/mp.2013.21. PMID: 23439485
Inositol pyrophosphates as mammalian cell signals. Chakraborty A, Kim S, Snyder SH. Sci Signal. 2011, 4, re1. PMID: 21878680 PMCID: PMC3667551
Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling. Prasad A, Jia Y, Chakraborty A, Li Y, Jain SK, Zhong J, Roy SG, Loison F, Mondal S, Sakai J, Blanchard C, Snyder SH, Luo HR. Nat Immunol. 2011, 12, 752-60. PMID: 21685907 PMCID: PMC3140608 DOI: 10.1038/ni.2052
Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. Chakraborty A, Werner JK Jr, Koldobskiy MA, Mustafa AK, Juluri KR, Pietropaoli J, Snowman AM,Snyder SH. Proc Natl Acad Sci U S A. 2011, 108, 2205-9.
Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. Kim S, Kim SF, Maag D, Maxwell MJ, Resnick AC, Juluri KR, Chakraborty A, Koldobskiy MA, Cha SH, Barrow R, Snowman AM, Snyder SH. Cell Metab. 2011, 13, 215-21.
Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Chakraborty A, Koldobskiy MA, Bello NT, Maxwell M, Potter JJ, Juluri KR, Maag D, Kim S, Huang AS, Dailey MJ, Saleh M, Snowman AM, Moran TH, Mezey E, Snyder SH. Cell 2010, 143, 897-910.
p53-mediated apoptosis requires inositol hexakisphosphate kinase-2. Koldobskiy MA, Chakraborty A, Werner JK Jr, Snowman AM, Juluri KR, Vandiver MS, Kim S, Heletz S, Snyder SH. Proc Natl Acad Sci U S A. 2010, 107, 20947-51.
Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition. Mustafa AK, van Rossum DB, Patterson RL, Maag D, Ehmsen JT, Gazi SK, Chakraborty A, Barrow RK, Amzel LM, Snyder SH. Proc Natl Acad Sci U S A. 2009, 106, 2921-6.
HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. Chakraborty A, Koldobskiy MA, Sixt KM, Juluri KR, Mustafa AK, Snowman AM, van Rossum DB, Patterson RL, Snyder SH. Proc Natl Acad Sci U S A. 2008, 105, 1134-9.
Inositol pyrophosphate pyrotechnics. Bhandari R, Chakraborty A, Snyder SH. Cell Metab. 2007, 5, 321-3.
Amino acid residues of Leishmania donovani cyclophilin key to interaction with its adenosine kinase: biological implications. Sen B, Venugopal V, Chakraborty A, Datta R, Dolai S, Banerjee R, Datta AK. Biochemistry 2007, 46, 7832-43.
Reversal of ADP-mediated aggregation of adenosine kinase by cyclophilin leads to its reactivation. Sen B, Chakraborty A, Datta R, Bhattacharyya D, Datta AK. Biochemistry 2006, 45, 263-71.
Homology-model-guided site-specific mutagenesis reveals the mechanisms of substrate binding and product-regulation of adenosine kinase from Leishmania donovani. Datta R, Das I, Sen B, Chakraborty A, Adak S, Mandal C, Datta AK. Biochem J. 2006, 394, 35-42.
Mutational analysis of the active-site residues crucial for catalytic activity of adenosine kinase from Leishmania donovani. Datta R, Das I, Sen B, Chakraborty A, Adak S, Mandal C, Datta AK. Biochem J. 2005, 387, 591-600.
Isomerase-independent chaperone function of cyclophilin ensures aggregation prevention of adenosine kinase both in vitro and under in vivo conditions. Chakraborty A, Sen B, Datta R, Datta AK. Biochemistry. 2004, 43, 11862-72.
A single-domain cyclophilin from Leishmania donovani reactivates soluble aggregates of adenosine kinase by isomerase-independent chaperone function. Chakraborty A, Das I, Datta R, Sen B, Bhattacharyya D, Mandal C, Datta AK. J Biol Chem. 2002, 277, 47451-60.