Center for Global Health Faculty

Assistant Scientist

Academic Degrees

• PhD
• MS

Departmental Affiliation

• Name:

  Environmental Health Sciences

  Affiliation Type:

  Primary

  Division:

  Toxicology

Departmental Address

Contact Information

Email:

rthimmul+jhsph.edu

Phone:

410-502-1949

Fax:

410-955-0116

Link:

SciVal Experts Research Profile

Research and Professional Experience

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.

Keywords

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

Honors and Awards

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

Selected Publications

1) 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. PMID: 21490276 (*Contributed equally)

2) Kong X*, Thimmulappa R*, Kombairaju P, and Biswal S. (2010) NADPH Oxidase-Dependent Reactive Oxygen Species Mediate Amplified TLR4 Signaling and Sepsis-Induced Mortality in Nrf2-deficient Mice. J Immunol 185(1):569-77. PMID: 20511556 (*Contributed equally)

3. 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. PMID: 20473305

4. Malhotra D*, Thimmulappa R*, Vij N, Sussan T, Merali S, Zhang L, 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. PMID: 19797762 (*Contributed equally)

 5. 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.

 6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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. (* Contributed equally)

12. 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.