My laboratory focus on the cys-LT-mediated signaling pathways and their role in asthma and allergic diseases that would help us devise potential therapeutic strategies. Cys-LTs comprises of LTC4, LTD4, LTE4, that are potent bronchoconstrictors and powerful inducers of vascular leakage, causing all the symptoms observed during asthma and inflammatory responses like wheezing, coughing and mucous production. High levels of cys-LTs are observed in fluids from patients with asthma after challenge with allergens, making these candidates attractive targets for the therapy of asthma. Drugs that block cys-LT synthesis or their receptors are currently being used in the therapy of asthma. However these drugs mainly target only two players of this pathway, LTC4 and LTD4, but not LTE4. My research demonstrated that signal transduction by LTE4 is unique from that of LTC4 or LTD4 (upstream intermediates) and that it has a distinctive role in inflammation. Recently, using a mouse asthma model system, we identified a third CysLT3 receptor activated by LTE4.
My current research mainly focuses on
1) Understanding the molecular mechanisms by which LTE4 induces pulmonary inflammation with special emphasis on targeting LTE4 as a therapy for asthma and other inflammatory disorders.
2) Identifying the novel cys-LT receptors and study their interaction with the prostaglandin receptors in mediating pulmonary inflammation
3) Elucidating the inhibitory/ enhancing function of these receptors on one another.
4) Investigating the role of putative LTE4 receptor in cardiovascular diseases
To achieve the above goals, my laboratory has expertise with cutting edge cell and molecular biological techniques as well as knock-out mouse models. In future, we would like to extend our studies to studying the receptor-ligand interactions using NMR spectroscopy to identify novel molecular targets down-stream of LTE4 receptor(s). These studies help us in better understanding and treatment strategies for asthma other than the conventional steroids that have lot of side effects.
- Laidlaw TM, Steinke J, Tiñana AM, Feng C, Xing W, Lam BK, Paruchuri S, Boyce JA, Borish L (2011) Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI. J Allergy Clin Immunol. 127(3):815-22
- Paruchuri S, Tashimo H, Feng C, Maekawa A, Xing W, Jiang Y, Kanaoka Y and Boyce JA (2009) Leukotriene E4-induced pulmonary inflammation is mediated by P2Y12 receptor. J Exp Med 206 (11):2543-55
- Paruchuri S, Jiang Y, Feng C, Francis SA, Plutzky J and Boyce JA (2008) Leukotriene E4 activates peroxisome proliferators-activated receptor gamma and induces prostaglandin D2 generation by human mast cells. J Biol Chem 283, 16477-87
- Melero-Martin JM, Khan ZA, Picard A, Wu X, Paruchuri S, Bischoff J. (2007) In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 109: 4761-8
- Paruchuri S, Yang J, Rabkin-Aikawa E, Melero Martin JM, Khan ZA, Loukogeorgakis S, Schoen FJ, Bischoff J (2006) Human pulmonary valve progenitor cells exhibit endothelial/ mesenchymal plasticity in response to VEGF-A and TGFb2. Circ Res 99:861-9
- Paruchuri S, Mezhybovska M, Juhas M, , Sjölander A. (2006) Endogenous production of leukotriene D4 mediated autocrine survival and proliferation via CysLT1 receptor signaling in intestinal epithelial cells. Oncogene 308:40-5
- Khan ZA, Melero-Martin JM, Wu X, Paruchuri S, Boscolo E, Mulliken JB, Bischoff J. (2006) Endothelial progenitor cells from infantile hemangioma and from umbilical cord blood display unique cellular responses to endostatin. Blood 108 (3):915-21
- Paruchuri S, Broom O, Dib K, Sjolander A. (2005). The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-Kinase and Rac-dependent migration of intestinal epithelial cells. J Biol Chem 280:13538-44
- Paruchuri S, Sjölander A. (2003) Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal epithelial cell line Int 407. J Biol Chem 278:45577-85
- Nielsen CK, Ohd JF, Wikstrom K, Massoumi R, Paruchuri S, Juhas M, Sjolander A. The leukotriene receptor CysLT1 and 5-lipoxygenase are upregulated in colon cancer. (2003) Adv Exp Med Biol 525:201-4.
- Paruchuri S, Hallberg B, Juhas M, Larsson C, Sjölander A (2002). Leukotriene D4 activates MAPK through a Ras-independent but PKC-dependent pathway in intestinal epithelial cells. J Cell Sci 115:1883-93
- Thodeti CK, Nielsen CK, Paruchuri S, Larsson C, Sjölander A.(2001) The epsilon isoform of protein kinase C is involved in the regulation of LTD4-induced calcium signal in human intestinal epithelial cells. Exp Cell Res 262:95-103
- Zeidman R, Petterson L, Sailaja PR, Truedsson E, Fagerstrom S, Pahlman S, Larsson C. (1999) Novel and Classical Protein Kinase C isoforms have different functions in proliferation, survival and differentiation of neuroblastoma cells. Int J Cancer 81, 494-501
- Chandrakala PS, Katz AK, Carrell HL, Sailaja PR, Podile AR, Nangia A, Desiraju GR (1998). Synthesis, X-ray crystal structures and biological evaluation of some mono- and bi-cyclic 1,3 diazetidin-2-ones: non natural beta lactum analogues. J Chem Soc Perkin Transactions 1:2597-608.