Department of Medicine
University of Pittsburgh
Division of Pulmonary, Allergy, and Critical Care Medicine3459 Fifth Avenue,
628 NW
Pittsburgh, PA 15213
Academic Office: (412) 692-2210
Comprehensive Lung Center (Patient Care and Referral): (412) 648-6161
Prabir Ray, PhD
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Professor of Medicine and Immunology Phone: 412-692-2118 |
Bio
Dr. Prabir Ray received his Ph.D. from Calcutta University in India. He received postdoctoral training at Cornell University, Ithaca, NY and at Sloan-Kettering Cancer Institute in New York. He was on the faculty at Yale University between 1990 and 2001 after which he joined the faculty in Pulmonary, Allergy and Critical Care Medicine with a co-appointment in the Department of Immunology at the University of Pittsburgh. Prabir Ray received his Ph.D. from Calcutta University in India. He received postdoctoral training at Cornell University, Ithaca, NY and at Sloan-Kettering Cancer Institute in New York. He was on the faculty at Yale University between 1990 and 2001 after which he joined the faculty in Pulmonary, Allergy and Critical Care Medicine with a co-appointment in the Department of Immunology at the University of Pittsburgh.
Academic and Research Interests
Research in Dr. Ray’s laboratory is focused on the following two major areas:
1) Effect of immunomodulatory agents (pathogens, drugs) on dendritic cell function influencing immune responses in the lung. Dendritic cells (DCs) and epithelial cells exist in close apposition in the lung. Drug therapy, allergen exposure or infection can alter the cytokine-chemokine milieu in the tissue. This altered microenvironment can influence DC function directly or indirectly via effects on epithelial cells or other cells of the innate immune system. Dr. Ray’s research has shown that statin, a cholesterol-lowering agent, can influence DC character and this statin-exposed DC induces a Th2 bias in the immune response (PNAS 103:7777, 2006). More recently, they have discovered that dual upregulation of the receptor tyrosine kinase, c-kit, and its ligand, stem cell factor (SCF), on DCs promotes Th2 and Th17 differentiation (Nature Medicine 14:565, 2008). This study highlights an important, previously unrecognized, role of c-kit in immunoregulation. Another focus of his ongoing studies is to understand mechanisms by which cells of the innate immune system influence adaptive immune responses in the lung using models of lung infection and allergic asthma.
2) Mechanisms by which growth factors protect the lung from acute lung injury and fibrosis. Because of its location and function, the lung is vulnerable to a variety of insults. Insults to the lung cause injury and abnormal repair of the injury can result in fibrosis, which inhibits normal lung function. Dr. Ray’s research has shown that some growth factors like keratinocyte growth factor (KGF), whose activity is largely restricted to epithelial cells, can protect the lung from injury and inhibit fibrosis. Using inducible transgenic and knockout mice, yeast two-hybrid system, microarray approaches and imaging technology they have been addressing the molecular mechanisms downstream of these biological signals that cause inhibition of lung injury and fibrosis (JEM 193: 545, 2001; PNAS, 100:6098, 2003). These studies show that specific signaling pathways induced in epithelial cells in the lung can protect the lung from a variety of insults including fibroproliferative responses. His current studies are directed towards understanding the role of epithelial cells in lung fibrosis and its prevention by specific growth factors.
Dual upregulation of c-kit and SCF in Dendritic cells regulate IL-6 production and expression of Notch ligand
Dendritic cells stimulated with Cholera Toxin, House Dust Mite or Prostaglandins upregulate expression of c-kit and membrane-bound SCF (mSCF), which is mediated by cAMP. c-kit activation by mSCF via cell-cell interaction triggers sustained downstream activation of the PI3 kinase/AKT pathway and possibly the MAPK and Jak-STAT pathways resulting in activation of NF-KappaBeta and production of IL-6. Activation of c-kit also upregulates Jagged-2 expression. The red arrows show known mechanisms of activation and the broken blue arrows indicate activation pathways for which the mechanisms have yet to be determined.
This schematic shows the design of an inducible lung-specific transgenic mouse overexpressing KGF in the lung (Ray et al., PNAS 100:6098, 2003). The system utilized the tet-inducible system and used a dual repressor-activator approach. The repressor was expressed to minimize leaky expression in the absence of Doxycycline (Dox) which would come off the promoter in the presence of Dox to allow the tet-activator to access the promoter and induce transgene expression. This system is based on the first lung-specific inducible transgenic mouse designed by our laboratory to express interleukin-11 in the lung (Ray et al., JCI 100:2501, 1997).
KGF activates Akt in epithelial cells and protects them for cell death induced by various insults including hyperoxia and chemotherapeutic agents such as bleomycin (Lu et al., J. Exp. Med. 193:54, 2001; Ray et al., PNAS 100:6098, 2003). KGF also exhibits anti-inflammatory effects as shown here where LPS-induced neutrophilic influx in the lung is significantly attenuated when KGF is overexpressed in situ.
Although statins are best known for their cholesterol-lowering effects, their immunomodulatory functions are being increasingly appreciated. In this study, we showed for the first time that simvastatin promotes expression of the chitinase family protein, Ym1, in dendritic cells (DCs), which in turn, promotes Th2 differentiation (Arora et al., PNAS 103:7777, 2006).
In this study, we have shown that the mucosal adjuvant cholera toxin (CT) and the allergen, house dust mite, upregulate expression of c-kit, its ligand, stem cell factor and in turn interleukin-6 in dendritic cells (DCs) which promotes Th2/Th17 responses and allergic airways disease (Krishnamoorthy et al., Nature Med 14:565, 2008). Shown here is the result of our microarray analysis that revealed increased IL-6 and c-kit mRNA expression in CT-treated DCs as compared to that in untreated controls. This observation prompted us to carry out an in-depth study of the significance of this finding.
This cartoon illustrates the signaling cascade induced in DCs when stimulated by allergen or cholera toxin causing increased iL-6 production from the DCs. IL-6 is central to Th17 differentiation and also promotes Th2 development both of which are associated with allergic airways disease (asthma).
Key Publications
Krishnamoorthy, N., Oriss, T.B., Paglia, M., Fei, M., Vanhaesebroeck, B., Ray, A. and Ray, P. (2008) Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nature Medicine 14:565-573.
Chen, Li, Arora, M., Yarlagadda, M., Oriss, T., Krishnamoorthy, N., Ray, A., Ray, P., (2006) Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide1. J. Immunol. 177: 2373-2383
Arora, M., Chen, L., Paglia, M., Gallagher, I., Allen, J.E., Vyas, Y.M., Ray, A., Ray, P., (2006) Simvastatin Promotes Th2-type Responses Through the Induction of Chitinase Family Member Ym1in Dendritic Cells. Proc. Natl. Acad. Sci. USA, 103:7777-7782.
Lu, Y., Pan, Z.Z., Devaux, Y., Ray P. (2003) PAK4 interacts with the keratinocyte growth factor receptor and participates in KGF-mediated inhibition of oxidant-induced cell death. J. Biol. Chem. 278:10374-10380
Ray, P., Devaux, Y., Stolz D.B., Yarlagadda, M., Watkins S.C, Liu, W., Lu, Y., Yang, X.F., Ray, A. (2003) Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia. Proc. Natl. Acad. Sci. USA, 100:6098-6103.
Lu, Y.B., Parkyn, L., Liu, W. Otterbein, L., Yang, L., Kureishi, Y., Walsh, K., Ray, P. (2001). Activated Akt protects the lung from oxidant-induced injury and delays death of mice. J. Exp. Med. 193: 545-549.
Yang. L., Cohn, L., Zhang, D. -H., Homer, R., Ray, A., Ray, P. (1998) Essential role of nuclear factor kappa beta in the induction of eosinophilia in allergic airway inflammation J. Exp. Med. 188: 1739-1750
PubMed Link
News
Dr. Ray is featured in many articles, including those below: