Shyam S. Biswal, PhD
Environmental Health Sciences
School of Medicine (Joint)
Center & Institute Affiliation(s):
PhD , Indian Institute of Technology , 1996
MS , Nagpur University
“Our laboratory is focused on discovering novel mechanisms of host defense that determine immunobiology and pathobiology of COPD and other environmental lung diseases to develop experimental therapeutics for their prevention and intervention in a susceptible population”.
Exposure to environmental toxicants and stressors such as cigarette smoke, indoor/outdoor air pollutants, respiratory bacteria/viruses and allergens causes oxidative/nitrosative stress, inflammation, and cell injury and is associated with diverse pulmonary disease states. In response to environmental stressors, cells activate transcription factor Nrf2 in lungs that confers host defense by upregulating multitude of cytoprotective genes. Suboptimal or inappropriate host defense predisposes to inflammation, oxidative/nitrosative stress and cell injury and thus play a critical role in determining susceptibility to various diseases. Decline in the Nrf2 pathway is associated with the progression of COPD and other lung diseases. We are developing molecular understanding of the host defense factor Nrf2 that upregulates stress response transcriptional program and protects against a range of pathological processes (oxidative stress, inflammation, and apoptosis) in environmental diseases such as COPD. A novel approach for prevention and intervention of COPD and other environmental lung diseases by augmenting Nrf2 is underway.
Environmental Health Sciences, cigarette smoke, lung diseases, inflammation, cancer, COPD, emphysema, asthma, environmental stress response
- Kim JH, Thimmulappa RK, Kumar K, Cui W, Kumar S, Kombairaju P, Gaiano N, Zhang H, Margolick J, Matsui W, Macvittie T, Malhotra SV, Biswal S. NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest. 2014;3;124(2):730-41.
- Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Wakabayashi N, Dewi R, Boros LG, Gonzalez FJ, Gabrielson E, Wong KK, Girnun G, Biswal S. Nrf2 regulates miR-1 and miR-206 to drive Tumorigenesis. J Clin Invest. 2013;123 (7) 2921-2934.
- Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A, Sathirapongsasuti JF, Cervo M, Yao H, Chung AL, Mizumura K, An CH, Shan B, Franks JM, Haley KJ, Owen CA, Tesfaigzi Y, Washko GR, Quackenbush J, Silverman EK, Rahman I, Kim HP, Mahmood A, Biswal SS, Ryter SW, Choi AM. J Clin Invest. 2013;123(12):5212-30.
- Harvey C, Thimmulappa R, Sethi S, Kong X, Yarmus L, Brown R, Feller-Kopman D, Wise R, and Biswal S. (2011) Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model. Sci Transl Med 3(78):78ra32.
- Malhotra D, Thimmulappa R, Mercado N, Ito K, Kombairaju P, Kumar S, Ma J, Feller-Kopman D, Wise R, Barnes P, and Biswal S. (2011) Denitrosylation of HDAC2 by Targeting Nrf2 Restores Glucocorticosteroid Sensitivity in Macrophages from COPD Patients. J Clin Invest. 121(11):4289-4302.
- Merchant A, Singh A, Matsui W, and Biswal S. (2011) The redox-sensitive transcription factor, Nrf2, regulates murine hematopoietic stem cell survival independent of ROS levels. Blood. 118:6572-6579.
- Wakabayashi N, Shin S, Slocum S, Agoston ES, Wakabayashi J, Kwak MK, Misra V, Biswal S, Yamamoto M, and Kensler TW. (2010) Regulation of Notch1 signaling by Nrf2: implications for tissue regeneration. Sci Signal 3(130):ra52.
- Yoshida T, Mett I, Bhunia A, Bowman J, Perez M, Zhang L, Gandjeva A, Zhen L, Chukwueke U, Mao T, Richter A, Brown E, Ashush H, Notkin N, Gelfand A, Thimmulappa R, Rangasamy T, Sussan T, Cosgrove G, Mouded M, Shapiro S, Petrache, Biswal S, Feinstein E, and Tuder R. (2010) RTP801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke induced pulmonary injury and emphysema. Nat Med 16(7):767-73.
- Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, and Biswal S. (2009) Targeting Nrf2 with the Triterpenoid CDDO-Imidazolide Attenuates Cigarette Smoke-Induced Emphysema and Cardiac Dysfunction in Mice. Proc. Natl Acad Sci. 106(1):250-5.
10. Malhotra D, Thimmulappa R, Vij N, Sussan T, Merali S, Zhang Li, Kelsen S, Myers A, Wise R, Tuder RM, and Biswal S. (2009) Heightened endoplasmic reticulum stress in COPD lungs: the role of Nrf2 regulated proteasomal activity. Am J Respir Crit Care Med. 180:1196-1207.
11. Podowski M, Calvi CL, Cheadle C, Tuder RM, Biswal S, Neptune ER. (2009) Complex integration of matrix, oxidative stress and apoptosis in genetic emphysema Am. J. Pathol. 175(1):84-96.
12. Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, and Biswal S. (2008) RNAi-mediated silencing of nuclear factor erythroid-2-related factor gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 68:(19): 7975-84.
13. Malhotra D, Thimmulappa RK, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, and Biswal S. (2008) Decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am J Respir Crit Care Med. 178(6):592-604.
14. Thimmulappa RK, Lee H, Rangasamy T, Kensler TW, Yamamoto M, Reddy SP, and Biswal S. (2006) Nrf2 is a critical regulator of innate immune response and survival during experimental sepsis. J. Clin. Invest. 116(4):984-995.
15. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman, JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S. (2006) Dysfunctional KEAP1 Nrf2 Interaction in Non-Small-Cell Lung Cancer. PLoS Medicine 3(10): e420.
16. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN and Biswal S. (2005) Disruption of Nrf2 Enhances susceptibility to Severe Airway Inflammation and Asthma in Mice. J. Exp. Med. 202(1):47-59.
17. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma S, Kensler TW, Yamamoto M, Petrache I, Tuder RM and Biswal S. (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice, J. Clin. Invest. 114(9):1248-1259.
18. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW Yamamoto M and Biswal S. (2002) Identification of Nrf2 Regulated Genes Induced by the Chemopreventive Agent Sulforaphane by Oligonucleotide Microarray. Cancer Res. 62(18):5196-5203.