My goal is to become a leading investigator in pulmonary immuno-metabolism at a top-tier academic research institution. This K22 Career Transition Award Application describes my training, career goals, plan for professional development, and an innovative research project that will put me in the ideal position to launch a successful independent program. Building off the strong scientific foundation I gained during my graduate and postdoctoral training, and with the full professional support of my mentor and the research communities here at Weill Cornell, I have identified new scientific challenges detailed in this application that I will address with cutting-edge tools and creative approaches. Chronic lung diseases such as asthma affect millions of Americans and yet current treatments can be ineffective, cause undesired side effects, and treat the symptoms rather than the cause. There is an urgent need to understand the molecular mechanisms controlling lung inflammation in order to design novel therapeutic strategies. Recent studies have demonstrated the importance of Group 2 innate lymphoid cells (ILC2s) in driving chronic lung inflammation including asthma; however, the mechanisms controlling this pro-inflammatory function are not well understood. In particular, whether ILC2 function is affected by changes in cellular metabolism is poorly understood. The central focus of this K22 Research Plan is to understand the cellular and biochemical mechanisms by which metabolic signals control innate immune-cell mediated lung inflammation. In new preliminary studies, I found that human and mouse lung ILC2s express a transcription factor called aryl hydrocarbon receptor (Ahr), which is a well-appreciated metabolic sensor of environmental-, diet-, and microbial-derived metabolites known to influence lung health and disease. Strikingly, mice deficient in Ahr had dysregulated ILC2 responses that resulted in protection from allergen-induced lung inflammation. Furthermore, I found that activation or inhibition of Ahr signaling directly regulated aspects of ILC2 metabolism, raising the hypothesis that Ahr-mediated changes to bioenergetic programming may underlie the ability of ILC2s to drive lung inflammation. Using cutting-edge techniques in metabolic profiling and immunobiology, in this proposal I will dissect the ILC2-Ahr-dependent mechanisms regulating lung tissue inflammation by investigating (1) How Ahr signaling affects ILC2 development, proliferation, and function in vitro and in vivo, and (2) how Ahr signaling affects ILC2 bioenergetics and the development of lung inflammation. Critically, this research project will generate rich metabolomic and sequencing data sets that will contribute to hypothesis generation for future NIH funding applications. Given my background training, publication record, grantmanship skills, mentorship experience of trainees, cutting-edge tools, and an extraordinarily supportive mentorship network, I am ideally-suited to take full advantage of this award to facilitate my pursuit of innovative scientific research and make meaningful discoveries in my independent program.

Public Health Relevance

Chronic inflammatory diseases of the lung are a major public health and economic concern worldwide and there is an urgent need for deeper understanding of the cellular and biochemical mechanisms that regulate lung inflammation in order to uncover novel targets to improve therapeutic treatments. An immune population called Group 2 innate lymphoid cells (ILC2s) have been shown to be critical in driving lung inflammation through production of type 2 cytokines; however, the molecular mechanisms controlling their functional capacity remain poorly understood. The focus of this K22 proposal is to investigate the role of a transcription factor metabolic `sensor' in regulating ILC2 function and bioenergetic programming during airway inflammation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K22)
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Allergy, Immunology, and Transplantation Research Committee (AITC)
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Gondre-Lewis, Timothy A
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Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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