University of Rochester
School of Medicine & Dentistry
Molecular Toxicology & Environmental Medicine Cluster
Ph.D. Program in Toxicology
*Steve N. Georas
Professor of Medicine and of Environmental Medicine
B.S. 1983, and M.D. 1987, Brown University
Director, Division of Pulmonary and Critical Care Medicine
E-Mail: steve_georas@urmc.rochester.edu

Molecular Mechanisms of Dysregulated Immune Responses in Asthma and Allergies

Our laboratory investigates the molecular mechanisms for dysregulated immune responses in asthma and allergic diseases. The lab consists of a dynamic and collaborative group of research technicians, post-doctoral fellows and students, and we have a long track record of mentorship in conducting translational studies bridging both basic and clinical research. Interested students or post-doctoral fellows are encouraged to apply for open positions. We are currently studying three related areas using both human cells and mouse models in an integrated fashion.
  • First, we have a long-standing interest in the molecular mechanisms of Th2 cytokine gene dysregulation in allergic diseases. We were one of the first groups to clone the human IL-4 promoter, and discovered several transcription factor binding sites contained therein. Ongoing studies are exploring chromatin-based and transcriptional pathways of IL-4 and IL-13 gene expression in T cells. These studies are conducted in collaboration with Dr. Jia Guo.

  • Second, we are studying how the innate immune system responds to inhaled particles and allergens. In collaboration with Dr. Marc Williams, we are testing the idea that dendritic cells sense and respond to ambient particulate matter as a pro-Th2 adjuvant. In ongoing studies, we are using mouse models of particulate matter exposure to study pathways of lung dendritic cell activation in situ, including the role of the “master anti-oxidant” transcription factor Nrf2 in this regard. These studies are conducted in collaboration with Dr. Tiru Rangasamy, Dr. Irfan Rahman, and Dr. Steve Kleeberger (NIEHS).

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  • Third, we are studying how the lysolipid lysophosphatidic acid (LPA) and its receptors regulate the activation of T cells and dendritic cells in asthma and inflammatory lung diseases. LPA is a normal component of serum, and we were the first to report that LPA is constitutively present in the human lung but increased during allergic inflammation. In ongoing studies we are testing the hypothesis that LPA is sensed as an “injury/repair” signal that promotes airway remodeling, and we are measuring LPA in clinical samples from human subjects with differing degrees of asthma severity. These studies are being conducted in collaboration with Dr. Viswanathan Natarajan (University of Chicago), investigators at GlaxoSmithKline, and Dr. Robert Block (URMC Lipidomics Consortium).

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Selected Publications

Porter M, Karp M, Killedar S, Bauer SM, Guo J, Williams D, Breysse P, Georas SN, Williams MA. Diesel-enriched particulate matter functionally activates human dendritic cells. Am J Respir Cell Mol Biol. 2007 Dec;37(6):706-719.

Georas SN, Berdyshev E, Hubbard W, Gorshkova IA, Usatyuk PV, Saatian B, Myers AC, Williams MA, Xiao HQ, Liu M, Natarajan V. Lysophosphatidic acid is detectable in human bronchoalveolar lavage fluids at baseline and increased after segmental allergen challenge. Clin Exp Allergy. 2007 Mar;37(3):311-322.

Williams MA, Porter M, Horton M, Guo J, Roman J, Williams D, Breysse P, Georas SN. Ambient particulate matter directs nonclassic dendritic cell activation and a mixed TH1/TH2-like cytokine response by naive CD4+ T cells. J Allergy Clin Immunol. 2007 Feb;119(2):488-497.

Chen R, Roman J, Guo J, West E, McDyer J, Williams MA, Georas SN. Lysophosphatidic acid modulates the activation of human monocyte-derived dendritic cells. Stem Cells Dev. 2006 Dec;15(6):797-804.

Saatian B, Zhao Y, He D, Georas SN, Watkins T, Spannhake EW, Natarajan V. Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. Biochem J. 2006 Feb 1;393(Pt 3):657-668.

Keen JC, Cianferoni A, Florio G, Guo J, Chen R, Roman J, Wills-Karp M, Casolaro V, Georas SN. Characterization of a novel PMA-inducible pathway of interleukin-13 gene expression in T cells. Immunology. 2006 Jan;117(1):29-37.

Georas SN, Guo J, De Fanis U, Casolaro V. T-helper cell type-2 regulation in allergic disease. Eur Respir J. 2005 Dec;26(6):1119-1137. Review.

Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005 Jul 4;202(1):47-59.

Hansel NN, Hilmer SC, Georas SN, Cope LM, Guo J, Irizarry RA, Diette GB. Oligonucleotide-microarray analysis of peripheral-blood lymphocytes in severe asthma. J Lab Clin Med. 2005 May;145(5):263-274.

Georas SN. Inhaled glucocorticoids, lymphocytes, and dendritic cells in asthma and obstructive lung diseases. Proc Am Thorac Soc. 2004;1(3):215-221. Review.

Heller NM, Matsukura S, Georas SN, Boothby MR, Stellato C, Schleimer RP. Assessment of signal transducer and activator of transcription 6 as a target of glucocorticoid action in human airway epithelial cells. Clin Exp Allergy. 2004 Nov;34(11):1690-1700.

Heller NM, Matsukura S, Georas SN, Boothby MR, Rothman PB, Stellato C, Schleimer RP. Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol. 2004 Nov;31(5):573-582.

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Revised February 6 2008 (vgl)