Research Summary

My long-term aim is to delineate sex-specific cellular and molecular pathways in stress-related pathophysiologies. I have a long-standing interest in understanding the regulation and action of neuropeptides during stress and inflammation, both in the central nervous system, and in the periphery. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and involvement of the corticotropin-releasing factor (CRF) system is pivotal step in stress response. CRF and urocortins are involved in mediating immune responses, but the molecular mechanisms involved and cellular pathways activated are unknown. A body of work from my laboratory has established how CRF receptor and their four different ligands that locally produced are sufficient to mediate signaling during stress and acute inflammatory stress using state-of-the-art techniques such as RNAi, electron & confocal microscopy, and mass spectrometry. In humans, stressors (perceived and psychological) are known to contribute to the development of metabolic syndrome and diabetes. Genome-wide association studies have identified several novel diabetes susceptibility loci including the stress receptor corticotropin-releasing factor receptor 2 (Crhr2). The stress receptor, CRF2, a key component of the stress hormone-receptor system that brings systems back to homeostasis once the stressors are removed. CRF2 dysfunction is seen in several of the chronic diseases associated with metabolic syndrome, cardiovascular disease, mood disorders, inflammation, and cancer. A body of work from my lab has shown that dysregulation of the stress receptor function causes organellar stress, distortion of endoplasmic reticulum ultrastructure to compromise protein quality and folding, increased basal mitochondrial respiration and shunting cells towards use of lactate as source of energy. These are all factors that serve as precursor to cells converting to cancerous state and maintain this balance is key for cells/systems becoming pathogenic or malignant.

Research Funding

  • May 1, 2014 - April 30, 2018 - Neuroplasticity of the gut-brain axis in functional dyspepsia , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK097518
  • April 1, 2008 - August 31, 2017 - Regulation and Function of Urocortins and their Receptor , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R56DK080787
  • April 1, 2009 - March 31, 2015 - Regulation and Function of Urocortins and their Receptors , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK080787
  • March 22, 2004 - February 28, 2007 - Site-specific Gene Silencing by RNA Interference , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21MH070650

Education

University of Rajasthan, India, B.S., 1986, Zoology (Honors)
University of Poona, India, M.S., 1988, Molecular Biology
University of Poona, India, Ph.D., 1995, Mol. & Dev. Biol.
New York Medical College, Valhalla, NY. Postdoc, 1995-1996, Mol. Biol.
University of California, San Francisco, CA, Postdoc, 1996-1999, Neuroendo. & Mol. Biol.

Honors & Awards

  • 1986 Certificate of Merit, University of Rajasthan, India. Awarded to top 5% BS (Honors) students
  • 1988 Graduate Research Fellowship. The Council of Scientific and Industrial Research (CSIR), India, awarded to top 2% of the students nationwide
  • 1992 UNESCO/TWAS Human Genome Fellowship Awarded to select candidates for obtaining specialized training at the University of Oxford, Oxford, United Kingdom
  • 1994 Senior Research Fellowship, Department of Biotechnology, Government of India
  • 2003 Quest Diagnostic Young Investigator Award, Endocrine Society
  • 2004 Young Investigator Travel Award, GIRI, Montreal Canada
  • 2006 Bavaria California Technology Award (BaCaTe)
  • 2010 New Investigator Award, American Physiological Society (Gastrointestinal& Liver Physiology section), Experimental Biology, April 24-28, 2010
  • 2010 FASEB MARC Travel Award, June 19-22, Endo 2010, San Diego
  • 2012 Fellow, American Gastroenterological Association (AGAF)
  • 2013 Nominated for the “2014 Ernest Oppenheimer Laureate Award”
  • 2014 Nominated for the “2015 Weitzman Award”, The Endocrine Society

Selected Publications

  1. Gandhi A, Tang R, Seo Y, Bhargava A. Organ-Specific Glucose Uptake: Does Sex Matter? Cells. 2022 07 16; 11(14).  View on PubMed
  2. Bhargava A, Fan S, Lujan CR, Fiehn O, Neylan TC, Inslicht SS. Chemical set enrichment analysis: Novel insights into sex-specific alterations in primary metabolites in posttraumatic stress and disturbed sleep. Clin Transl Med. 2021 12; 11(12):e511.  View on PubMed
  3. Qu J, Fourman S, Fitzgerald M, Liu M, Nair S, Oses-Prieto J, Burlingame A, Morris JH, Davidson WS, Tso P, Bhargava A. Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue. Sci Rep. 2021 06 24; 11(1):13289.  View on PubMed
  4. Murray I, Bhanot G, Bhargava A. Neuron-Glia-Immune Triad and Cortico-Limbic System in Pathology of Pain. Cells. 2021 06 19; 10(6).  View on PubMed
  5. Bell RL, Withers GS, Kuypers FA, Stehr W, Bhargava A. Stress and corticotropin releasing factor (CRF) promote necrotizing enterocolitis in a formula-fed neonatal rat model. PLoS One. 2021; 16(6):e0246412.  View on PubMed
  6. Bhargava A, Arnold AP, Bangasser DA, Denton KM, Gupta A, Hilliard Krause LM, Mayer EA, McCarthy M, Miller WL, Raznahan A, Verma R. Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement. Endocr Rev. 2021 05 25; 42(3):219-258.  View on PubMed
  7. Cordner ZA, Li Q, Liu L, Tamashiro KL, Bhargava A, Moran TH, Pasricha PJ. Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model. JCI Insight. 2021 03 22; 6(6).  View on PubMed
  8. Vuppaladhadiam L, Lager J, Fiehn O, Weiss S, Chesney M, Hasdemir B, Bhargava A. Human Placenta Buffers the Fetus from Adverse Effects of Perceived Maternal Stress. Cells. 2021 02 12; 10(2).  View on PubMed
  9. Liu S, Karo A, Agterberg S, Hua H, Bhargava A. Effects of stress-related peptides on chloride secretion in the mouse proximal colon. Neurogastroenterol Motil. 2021 04; 33(4):e14021.  View on PubMed
  10. Vuppaladhadiam L, Ehsan C, Akkati M, Bhargava A. Corticotropin-Releasing Factor Family: A Stress Hormone-Receptor System's Emerging Role in Mediating Sex-Specific Signaling. Cells. 2020 03 31; 9(4).  View on PubMed
  11. Yuan J, Hasdemir B, Tan T, Chheda C, Rivier J, Pandol SJ, Bhargava A. Protective effects of urocortin 2 against caerulein-induced acute pancreatitis. PLoS One. 2019; 14(5):e0217065.  View on PubMed
  12. Qu J, Ko CW, Tso P, Bhargava A. Apolipoprotein A-IV: A Multifunctional Protein Involved in Protection against Atherosclerosis and Diabetes. Cells. 2019 04 05; 8(4).  View on PubMed
  13. Hagiwara SI, Hasdemir B, Heyman MB, Chang L, Bhargava A. Plasma Corticotropin-Releasing Factor Receptors and B7-2⁺ Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity. Cells. 2019 01 30; 8(2).  View on PubMed
  14. Hasdemir B, Oses-Prieto JA, Burlingame A, Bhargava A. Probing the Interactome of Corticotropin-Releasing Factor Receptor Heteromers Using Mass Spectrometry. Methods Mol Biol. 2019; 1947:269-285.  View on PubMed
  15. D'Costa S, Ayyadurai S, Gibson AJ, Mackey E, Rajput M, Sommerville LJ, Wilson N, Li Y, Kubat E, Kumar A, Subramanian H, Bhargava A, Moeser AJ. Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability. J Allergy Clin Immunol. 2019 05; 143(5):1865-1877.e4.  View on PubMed
  16. Paruthiyil S, Hagiwara SI, Kundassery K, Bhargava A. Sexually dimorphic metabolic responses mediated by CRF2 receptor during nutritional stress in mice. Biol Sex Differ. 2018 11 06; 9(1):49.  View on PubMed
  17. Hagiwara SI, Kaushal E, Paruthiyil S, Pasricha PJ, Hasdemir B, Bhargava A. Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia. PLoS One. 2018; 13(9):e0203704.  View on PubMed
  18. Strumwasser A, Bhargava A, Victorino GP. Attenuation of endothelial phosphatidylserine exposure decreases ischemia-reperfusion induced changes in microvascular permeability. J Trauma Acute Care Surg. 2018 06; 84(6):838-846.  View on PubMed
  19. Hasdemir B, Mahajan S, Oses-Prieto J, Chand S, Woolley M, Burlingame A, Grammatopoulos DK, Bhargava A. Actin cytoskeleton-dependent regulation of corticotropin-releasing factor receptor heteromers. Mol Biol Cell. 2017 Sep 01; 28(18):2386-2399.  View on PubMed
  20. Gurfein BT, Hasdemir B, Milush JM, Touma C, Palme R, Nixon DF, Darcel N, Hecht FM, Bhargava A. Enriched environment and stress exposure influence splenic B lymphocyte composition. PLoS One. 2017; 12(7):e0180771.  View on PubMed

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