The proposed study describes a 4-year training plan for the development of an academic with a research focus on the mechanisms that underlie influenza virus induced pulmonary inflammation. The candidate, Shaon Sengupta is an attending neonatologist at the Neonatal Intensive Care Unit (NICU) of the Children's Hospital of Philadelphia. She has extended her training by engaging in intensive basic science research supported by the Ruth L. Kirschstein National Research Service Award (T32), and continues to be supported by the Department of Pediatrics Child Health Research Career Development Award (K12). This work will be carried out under the mentorship of Garret A. FitzGerald, M.D. a leader in the fields of circadian rhythms of peripheral clocks and a pioneer in prostanoid biology. He is the Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine, and the director of ITMAT and has an outstanding track record for mentorship. Influenza A virus (IAV) infection is a major infectious cause of pulmonary morbidity and mortality in the world. Recent clinical studies suggest that the response to influenza vaccine depends on the time of day at which the vaccine was administered. Further, Dr. Sengupta has generated preliminary data, proving that the response of the lung to IAV depends on the time at which the animal was exposed to IAV. Most diurnal variations in signs, symptoms or response to therapy are generated by the influence of the circadian system. However, the role of circadian rhythms in IAV pathogenesis is not known. The goals of the proposed work are: 1. To determine the mechanisms underlying the diurnal variation in the immune response to IAV infection. 2. To test the hypothesis that the circadian clock is responsible for the diurnal variation in IAV-induced lung injury and mortality, by a. Determining if the loss of core clock gene Bmal1 amplifies the severity and abrogates the diurnal difference in IAV induced lung injury. b. Determining the cellular mechanisms underlying the circadian control of IAV induced inflammation. This will be achieved by investigating whether the loss Bmal1 in myeloid cells (LysMCreBmal1-/- mice-- innate immune clock) or in the lung epithelium (CCSPCreBmal1-/- mice) leads to the amplified severity and loss of clock gating to IAV. 3. To test if a disruption of the circadian control over the response to IAV infection underlies the increase in post-viral airway hyper-reactivity (AHR). Completion of the proposed work is expected to provide novel insights into the circadian regulatory components that determine host response, post viral AHR and lung inflammation in IAV.
The aim of the proposed work is to provide mechanistic understanding of the immune pathways and the circadian influence over these pathways that determines the diurnal variation in response to acute IAV infection as well as associated chronic morbidities such as AHR.