Appropriate cellular stress response to environmental stressors (pathogen and non-pathogen) is critical to counteract the stress and protect against a range of pathological process that promotes pathogenesis of disease. My research focus has been in understanding host factors specifically transcription factor Nrf2, that regulate redox-dependent stress response signaling pathway and alter the susceptibility to and severity of inflammatory disorders. Our interest has been to find: How cellular redox status modulate inflammatory and or oxidative stress signal transduction pathways? Can “redox status” be critical variable in determining the susceptibility to inflammatory and oxidative stress disorders caused by pathogen as well as non-pathogen? Can correction of “redox perturbations” by antioxidant therapy alleviate the inflammatory and oxidative stress disorders that involve immune dysfunction? We have found that Nrf2, a bzip transcription factor gets activated in response cellular redox changes and upregulates a cytoprotective stress response pathway that includes antioxidants, anti-inflammatory and antimicrobial defenses. My current research focuses on: i) understand the Nrf2-mediated redox modulation of cellular stress response pathway in response to diverse environmental stressors (pathogen and non-pathogen); ii) understand the significance of Nrf2 pathway in determining susceptibility to and severity of inflammatory disorders specifically COPD and sepsis; iii) develop Nrf2 targeted therapy (using pharmacological small molecule activators) for intervention of acute and chronic inflammatory disorders. Nrf2 based therapy may provide robust protection against environmental toxicants (chemical and pathogens) by mediating heightened cytoprotection and balanced immune response in healthy and high-risk subject population.

Nrf2, COPD, ALI, Sepsis, Innate immunity, oxidative stress

1. Junior Research Fellowship and Senior Research fellowship awarded by Council of Scientific and Industrial Research, Ministry of Science, Government of India, India.

2. Merit and Endowment prize award for ‘First’ in B.S degree honored by The National College, Bangalore, Karnataka, India

3. Post Doctoral investigator Award by ‘American Institute for Cancer Research’ (AICR)

4. Highly cited “Research article” by Thompson ISI, 2005. Publication in “Cancer Research” Journal was recognized as one of highly cited (placed it in the top 1% within its field) article according to “Essential Science Indicators”, Thompson, ISI (isiknowledge.com)

5. Young Clinical Scientist Award from Flight Attendant Medical Research Institute (FAMRI)- 2009

1. Nagai N, Thimmulappa RK, Cano M, Fujihara M, Izumi-Nagai K, Kong X, Sporn MB, Kensler TW, Biswal S, Handa JT. Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic Biol Med. 2009 Aug 1;47(3):300-6.

2. McGrath-Morrow S, Lauer T, Yee M, Neptune E, Podowski M, Thimmulappa RK, O'Reilly MA, Biswal S. Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol. (2009) [Epub ahead of print]

3. Sussan TE, Jun J, Thimmulappa R, Bedja D, Antero M, Gabrielson KL, Polotsky VY, Biswal S, Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. PLoS ONE. 2008;3(11):e3791.

4. Harvey CJ, Thimmulappa RK, Singh A, Blake DH, Ling G, Wakabayashi N, Fujii J, Myers AC, and Biswal S. Nrf2 regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Rad Biol Med (2008)

5. Singh A, Adamsky S, Thimmulappa RK, Rath S, Ashush A, Coulter J, Blackford A, Goodman S, Watson W, Bunz F, Gabrielson E, Feinstein E, Biswal S. RNAi mediated silencing of Nrf2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res, (2008) 68(19):7975-84.

6. Malhotra D*, Thimmulappa R*, Navas-Acien A., Sandford A, Elliot M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S. Decline in Nrf2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am. J. Respir. Crit. Care. Med. (2008) 178(6):592-604.

7. Traore K, Sharma R, Thimmulappa RK, Watson WH, Biswal S, Trush MA. Redox-regulation of Erk1/2-directed phosphatase by reactive oxygen species: Role in signaling TPA-induced growth arrest in ML-1 cells. J Cell Physiol. (2008) 216(1):276-85

8. Thimmulappa, R.K., Rangasamy, T., Alam, J, Biswal, S. Dibenzoylmethane activates Nrf2-dependent detoxification pathway and inhibits benzo(a)pyrene induced DNA Adducts in lungs Medicinal Chemistry (2008) 4(5):473-81

9. Misra V, Lee H, Singh A, Huang K, Thimmulappa RK, Mitzner W, Biswal S, Tankersley CG. Global Expression Profiles from C57BL/6J and DBA/2J Mouse Lungs to Determine Aging-related Genes. Physiol. Genomics. (2007) 31(3):429-40

10. Thimmulappa, R.K, Fuchs R.J, Malhotra, D, Scollick, C., Trarore, K., Bream J.H, Trush M.A., Liby K.T., Spoorn, M., Kensler,T.W and Biswal,S., Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal (2007) 9:1963-70.

11. Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW , Yamamoto M, Biswal S, Dor´e S Role of Nrf2 in Protection against Intracerebral Hemorrhage Injury in Mice. Free Radic Biol Med. (2007) 102(4):1632-9.

12. Shah ZA, Li RC, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Dore S. Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience. (2007) 147(1):53-9

13. Rajesh K. Thimmulappa, Scollick, C., Trarore, K., Yates, M., Trush M.A., Liby K.T., Spoorn, M., Yamamoto,M., Kensler,T.W and Biswal,S., Nrf2 dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun (2006) 351: 883-889.

14. Anju Singh, Vikas Misra, Rajesh K. Thimmulappa, Hannah Lee, Stephen Ames, Mohammad O. Hoque, James G. Herman, Stephen B. Baylin, David Sidransky, Edward Gabrielson2, Malcolm Brock, Shyam Biswal, Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer. PLoS Med. (2006) 3(10) :1865-1876.

15. Singh A, Tirumalai Rangasamy, Rajesh K Thimmulappa, Hannah Lee, Regina Brigelius-FLohe, Thomas W. Kensler, Masayuki Yamamoto and Shyam Biswal. Regulation of the major cigarettes smoke-inducible isoform of glutathione peroxidase, GPx2, in lungs by Nrf2. Am J Respir Cell Mol Biol. (2006) 35(6) :639-50.

16. Rajesh K Thimmulappa, Hannah Lee, Tirumalai Rangasamy, Shekar Reddy, Thomas W. Kensler, Masayuki Yamamoto, and Shyam Biswal, Nrf2 is a critical regulator of innate immune response and survival during experimental sepsis. J Clin Invest. (2006) 116(4) :984-95.

17. Rangasamy T, Cho CY *, Rajesh K Thimmulappa *, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. (2004) 114(9)1248-59.

18. Rajesh K Thimmulappa, Kim Mai, S. Srisuma, Kensler, T.W., Yamamoto, M and SS Biswal, Identification of Nrf2 Regulated Genes by Oligonucleotide Microarray: Potential Role in Cancer Chemoprevention. Cancer Res. (2002) 62(18) 5196-203.