Dr. Sekhar Reddy
Associate Professor of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
Joint Appointment in Oncology
Ph.D., University of Hyderabad
My lab research primarily focuses on elucidating the molecular mechanisms underlying environmental toxin-induced respiratory pathogenesis, including lung cancer.
In the primary area of research, our lab studies are focused on the molecular mechanisms underlying cigarette smoke-induced respiratory pathogenesis. "Squamous cell metaplasia" and "hyperplasia" of airway epithelium have been considered to be among the pre-neoplastic stages that may lead to bronchogenic cancer. Recently, we have shown that the c-Jun:Fra-1-based activator protein 1 (AP-1) complex plays a critical role in tumor promoter- and cigarette smoke-induced expression of the squamous differentiation marker, SPRR1B, in bronchial epithelial cells. AP-1 acts as one of the environmental biosensors that participate in cellular switching of the genetic program in response to various toxic and mitogenic stimuli. However, the physiological relevance and specific contribution of individual AP-1 family members to lung biology and toxicant-induced respiratory pathogenesis remain enigmatic.
Emerging evidence indicates that Fra-1 plays a key role in pulmonary defense, injury, and repair processes, as well as tumor progression. Fra-1 is not only over-expressed in a wide variety of tumors and malignant cells but also causally linked to the up-regulation of genes associated with tumor progression and invasiveness. Currently, we are elucidating both transcriptional and signal transduction pathways regulating the induction of Fra-1 by various toxicants, including cigarette smoke. Also, transgenic mouse models are being utilized to better understand the functional role of Fra-1 in lung injury, repair, and cellular transformation. These studies may lead to the development of novel treatment strategies against toxicant-induced respiratory pathogenesis.
In our secondary area of research, we are using molecular approaches to understand the mechanisms involved in oxidant (hyperoxia) and mechanical ventilation-induced lung injury. Many pulmonary diseases, including acute respiratory distress syndrome (ARDS) and emphysema, require oxygen supplementation (or hyperoxia) to maintain adequate tissue oxygenation. However, hyperoxia causes extensive pulmonary damage that is characterized by inflammation and endothelial and alveolar epithelial cell death, resulting in pulmonary edema and respiratory dysfunction. We have recently shown that mice lacking the NF-E2-related transcription factor 2 (Nrf2) are more susceptible to hyperoxia than are wild-type mice. Nrf2 activates antioxidant and detoxifying enzyme gene expression to provide protection against toxic oxidant insults. Our research is currently focused on elucidating upstream signaling mechanisms that control the activation of Nrf2 and its downstream effectors, as a means of gaining insight into the pathogenesis of acute lung injury. This endeavor may not only help us devise new strategies to minimize the potentially hazardous effects of hyperoxia but may also lead to new therapeutic strategies aimed at minimizing the excessive morbidity and mortality associated with acute lung injury.
Zhang Q, Adiseshaiah P, and Reddy, SPM (2004). Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 Induction by cigarette smoke in lung epithelial cells. Am J Respir Cell Mol Biol. 2004 Nov 4; [Epub ahead of print]
Cho, H-Y., Reddy, SP, DeBiase, A., Yamamoto, M and Kleeberger SR (2004). Gene expression profiling of Nrf2-mediated protection against oxidative injury. Free Radicals in Biology and Medicine (In Press), Available online 12 November 2004
Papaiahgari SR, Kleeberger SR, Cho H-Y, Kalvakolanu DV, and Reddy, SP. (2004) NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells. J Biol Chem. 279:42302-12.
Cho H-Y, Reddy SP, Yamamoto M, and Kleeberger SR (2004) The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 18:1258-60
Zhang Q, Kleeberger SR, and Reddy, SPM (2004). Diesel exhaust particles (DEP)-induced fra-1 expression correlates with a distinct activation of AP1-dependent gene transcription in the lung. AJP: Lung Cellular and Molecular Physiology, 286: L427-L436.
Adiseshaiah P, Papaiahgari SR, Vuong H, Kalvakolanu DV, and Reddy, SPM (2003) Multiple cis-elements mediate the transcriptional activation of human fra-1 by 12-O-tetradecanoylphorbol-13-acetate in bronchial epithelial cells. Journal of Biological Chemistry 278:47423-33
Reddy, SPM, Vuong, H. and Adishesaiah, P (2003) Interplay between proximal and distal promoter elements is required for squamous differentiation marker expression in bronchial epithelium: Role for ETS, Sp1 and AP-1 proteins. Journal of Biological Chemistry 278:21378-87
Roy, S., Hu, J., Meng, Q., Xia, Y., Shapiro, P., Reddy, SPM, Platanias, L., lindner, D.J., Johnson PF., Pritchard C, Pages G, Pouyssegur J and Kalvakolanu, D. V. (2003) MEKK1 plays a crtical role in activating the transcription factor C/EBP-beta dependent gene expression in response to IFN-gamma. Proc. Natl. Acad. Sci., USA 99: 7945-50
Reddy, SPM and Mossman B.T (2002) Role and regulation of activator protein-1 in toxicant-induced responses of the lung. AJP: Lung Cellular and Mol. Physiology 283: L1161-L1178. Invited Review.
Reddy, SPM., Adishesaih., Shapiro, and Vuong, H. (2002). ERK5 (BMK1) regulates squamous differentiation marker, SPRR1B, expression in Clara-like H441 cells. American Journal of Respiratory Cell and Molecular Biol 27: 64-70
Spannhake, W, Reddy, SPM., Jacoby, D., Yu, XY, Saatian B, and Tian, J. (2002) Synergism between rhinovirus infection and oxidant pollutant exposure enhances airway epithelial cell cytokine production. Environmental Health Perspectives 110, 665-670.
Chang, W-H., Reddy, SPM, Y.-P. Di, Yoneda, K., and R. Wu. (2002). An unusual participation of four RARE-like half sites in the regulation of both basal and retinoid enhanced human thioredoxin gene expression. American Journal of Respiratory and Cell and Molecular Biology 26, 627-635.
Vuong, H., Patterson, T., Adishesaih., Shapiro, P., Kalvakolanu, D.V., and Reddy, SPM (2002). JNK1 and AP-1 regulate PMA inducible squamous cell differentiation marker expression in Clara-like H441 cells. AJP: Lung Cellular and Molecular Physiology 282: 226-236.
Cho, H-Y., A.E. Jedlicka., Reddy, SPM., Kensler, T.W., Yamamoto, M., Zhang, L.-Y., and Kleeberger, S.R. (2002). Linkage analysis of susceptibility to hyperoxia: NRF2 is a candidate gene. Respiratory American Journal of Respiratory Cell and Molecular Biology 26: 42-51.
Cho, H-Y., A.E. Jedlicka., Reddy, SPM, Kensler, T.W., Yamamoto, M., Zhang, L.-Y., and Kleeberger, S.R. (2002). Role of NRF2 in protection against hyperoxic lung injury in mice. American Journal of Respiratory and Cell and Molecular Biology 26: 175-182.
Patterson, T., Vuong, H., Liaw, Y-S., Wu, R., Kalvakolanu, D. V., and Reddy, SPM (2001). Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: Role of critical TRE-sites and its transacting factors. Oncogene. 20: 634-654.
Ma, X., Karra, S., Lindner, DJ., Hu, J., Reddy, SPM., Kimchi A., Yodoi, J., and Kalvakolanu, D. V. (2001). Thioredoxin participates in a cell death pathway induced by intereferon and retinoid combination. Oncogene 20:3703-3715.
Ma, X., Karra, S., Guo. W., Lindner, DJ., Hu, J., Hofmann, ER., Angell JE., Reddy, SPM., and Kalvakolanu, D. V. (2001). Mechanism of intereferon and retinoic acid induced cell death activation through thioredoxin reductase. Journal of Biological Chemistry 276: 24843-24854.
Kleeberger, S.R., Reddy, SPM ., Zhang, L.-Y. and Jedlicka, A.E. (2000). Genetic susceptibility to ozone-induced lung hyperpermeability: Role of the toll-like receptor 4 (Tlr4). American Journal of Respiratory and Cell and Molecular Biology. 22: 620-627.
Vuong, H., Patterson, T., Shapiro, P., Kalvakolanu, D. V., Dong, Z., Wei-Ma Ya, Wu. R , Kleeberger, S.R., and Reddy, SPM (2000). Phorbol ester induced expression of airway squamous cell differentiation marker, SPRR1B, gene is regulated by PKC delta-RAS-MEKK1-MEK1-dependent /AP-1 signal transduction pathway. Journal of Biological Chemistry 275: 32250-32259.
Lau, D., Xue, L., Hu, R. Liaw, T., Wu. R., and Reddy, SPM ., (2000) Expression and regulation of a molecular marker, SPR1, in multistep bronchial carcinogenesis. American Journal of Respiratory and Cell and Molecular Biology 22: 92-96.
Reddy, SPM ., Konkin, T. and R. Wu. (1998) Structure and organization of the genes encoding a mouse small proline-rich proteins, mSPRR1A and 1B. GENE 224, 59-66.
Reddy, SPM ., G. An, Y.P. Di, Y.H. Zhao, and R. Wu (1996). Isolation and characterization of nucleolin gene as one of the vitamin A-responsive genes in airway epithelium by a palindromic primerbased mRNA differential display method. American Journal of Respiratory and Cell and Molecular Biology 15: 398-403.
Reddy, SPM ., Y.J. Chuu, P.N. Lao, J.Donn, D.K. Ann and R. Wu (1995). Expression of human squamous cell marker, spr1, in tracheobronchial epithelium depends on JUN and TRE motifs. Journal of Biological Chemistry 270: 2645126459.
Reddy, SPM ., C.P. Tu, and R. Wu (1995). Glutathione Stransferases in tracheobronchial epithelium: Differential expression and regulation by vitamin A and collagen substratum. AJP: Lung Cellular and Molecular Physiology, 269: L473L481.