Rajesh K. Thimmulappa, PhD
Center & Institute Affiliation(s):
615 N.wolfe street, Hygiene building, Room #W7714
Baltimore , Maryland 21205
PhD , 2002
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.
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
Nrf2, COPD, ALI, Sepsis, Innate immunity, oxidative stress
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. (*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.