Dr. Murugappan Ramanathan is a junior faculty member in the Department of Otolaryngology-Head &Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to the medical and surgical management of nasal and sinus disorders. His previous research focused on impaired sinonasal epithelial innate immune responses in patients with chronic sinusitis. With the support of this Mentored Career Development Award, Dr. Ramanathan seeks to better understand the impact of indoor environmental exposure (particulate matter and allergens) on oxidative stress based sinonasal inflammation regulated by the Nrf2 anti- oxidant pathway. Dr. Ramanathan will enhance his research knowledge and skills with coursework in environmental health and air pollution, receive directed mentorship by an interdisciplinary team of experienced researchers, and be immersed in the interdisciplinary research and clinical environments of the Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, and the Center for Childhood Asthma in the Urban Environment. This Career Development Award will provide Dr. Ramanathan with the resources that he needs to become an independent investigator and future leader in environmental exposure related sinonasal inflammation research. Building on his prior research experience in chronic sinonasal inflammation, Dr. Ramanathan has now transitioned his focus towards examining how the indoor environmental pollutants and allergens propagate oxidative stress related sinonasal inflammation. He is also interested in how the novel drug targetable transcription factor, Nrf2, may control the mucosal inflammatory state.
In Aim 1 a, he will determine the role of Nrf2 in regulating indoor particulate matter (PM) induced sinonasal inflammation in an allergic rhinitis mouse model.
Aim 1 b will use sinonasal epithelial cells grown in culture from control and chronic sinusitis patients and expose them in vitro to indoor PM or environmental mouse allergen. Subsequently, levels of inflammation, oxidative stress, and Nrf2 dependent antioxidants will be measured.
In Aim 1 c, Dr. Ramanathan will use asthmatic patients from the existing NIEHS ASTHMA-DIET study and correlate sinonasal levels of inflammation, oxidative stress, and levels of Nrf2 regulated antioxidants after intranasal mouse allergen challenge. Finally, in Aim 2, Dr. Ramanathan will use sulforaphane for chemoprotection to enhance levels of Nrf2 regulated antioxidants in both animal and cell culture models prior to environmental exposures. The process of performing these experiments will provide the candidate with the necessary guidance, coursework, and practical training towards becoming an independent investigator as well as furthering the basic science knowledge of sinonasal inflammation. Public Health Relevance: Chronic rhinosinusitis afflicts greater than 30 million individuals yearly and is among the most common conditions for which patients seek medical care in the US. While the pathogenesis of this disease is multi-factorial, very little research has examined the role of environmental exposure. This proposal will study the role of a critical pathway that may regulate environmentally induced inflammation in the nose and sinus and may ultimately lead to more effective therapies for chronic sinusitis.

Public Health Relevance

Chronic rhinosinusitis afflicts greater than 30 million individuals yearly and is among the most common conditions for which patients seek medical care in the US. While the pathogenesis of this disease is multi-factorial, very little research has examined the role of environmental exposure. This proposal will study the role of a critical pathway that may regulate environmentally induced inflammation in the nose and sinus and may ultimately lead to more effective therapies for chronic sinusitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23ES020859-03
Application #
8475599
Study Section
Special Emphasis Panel (ZES1-LKB-J (K9))
Program Officer
Shreffler, Carol K
Project Start
2011-09-16
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$249,229
Indirect Cost
$18,461
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bose, Sonali; Romero, Karina; Psoter, Kevin J et al. (2018) Association of traffic air pollution and rhinitis quality of life in Peruvian children with asthma. PLoS One 13:e0193910
London Jr, Nyall R; Ramanathan Jr, Murugappan (2018) Sinuses and Common Rhinologic Conditions. Med Clin North Am 102:993-1000
Tharakan, Anuj; Dobzanski, Alex; London Jr, Nyall R et al. (2018) Characterization of a novel, papain-inducible murine model of eosinophilic rhinosinusitis. Int Forum Allergy Rhinol 8:513-521
Ramanathan Jr, Murugappan Murray; Mims, James W (2017) Allergy for the Otolaryngologist. Otolaryngol Clin North Am 50:xvii-xviii
Kohanski, Michael A; Tharakan, Anuj; London, Nyall R et al. (2017) Bactericidal antibiotics promote oxidative damage and programmed cell death in sinonasal epithelial cells. Int Forum Allergy Rhinol 7:359-364
Ramanathan Jr, Murugappan; London Jr, Nyall R; Tharakan, Anuj et al. (2017) Airborne Particulate Matter Induces Nonallergic Eosinophilic Sinonasal Inflammation in Mice. Am J Respir Cell Mol Biol 57:59-65
London Jr, Nyall R; Ramanathan Jr, Murugappan (2017) The Role of the Sinonasal Epithelium in Allergic Rhinitis. Otolaryngol Clin North Am 50:1043-1050
London Jr, Nyall R; Tharakan, Anuj; Rule, Ana M et al. (2016) Air pollutant-mediated disruption of sinonasal epithelial cell barrier function is reversed by activation of the Nrf2 pathway. J Allergy Clin Immunol 138:1736-1738.e4
Tharakan, Anuj; Halderman, Ashleigh A; Lane, Andrew P et al. (2016) Reversal of cigarette smoke extract-induced sinonasal epithelial cell barrier dysfunction through Nrf2 Activation. Int Forum Allergy Rhinol 6:1145-1150
Mendiola, Michelle; Tharakan, Anuj; Chen, Mengfei et al. (2016) Characterization of a novel high-dose ovalbumin-induced murine model of allergic sinonasal inflammation. Int Forum Allergy Rhinol 6:964-72

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