[K01] Neutrophil-targeted therapy for severe asthma
Ente: NIH Office of the Director
Scadenza: 2031-06-30
Importo max: 135.558 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
This Mentored Research Scientist Development Award (K01) will support Dr. Rosemary Bayless, DVM, MS,
PhD, DACVIM (LAIM), as she establishes her independent research career studying novel therapies for
neutrophilic asthma and other neutrophil-mediated diseases in human patients. Dr. Bayless’ specialized training
in veterinary comparative medicine, equine internal medicine and inflammatory pathophysiology make her
uniquely qualified to advance translational research by leveraging both experimental and spontaneous
models of human inflammatory diseases. The proposed aims and training plan, focusing on the mechanisms
of a novel therapeutic for neutrophilic asthma, were carefully designed to provide Dr. Bayless with advanced
training in 3D in vitro models, co-culture systems, and preclinical murine models, as well as study design and
grant writing. Through mentorship from basic and translational research experts, established physician-
scientists, and an experienced biostatistician, Dr. Bayless will develop key skills that will help launch a
successful research-intensive career as an independent R01-funded translational clinician-scientist.
The proposed training project addresses asthma, a chronic, progressive, debilitating respiratory disease.
Asthmatic patients with neutrophilic airway inflammation tend to have more severe and treatment-resistant
clinical signs compared to those with eosinophilic asthma. Novel asthma therapies that target neutrophilic
inflammation would benefit millions of patients around the world. Withaferin A (WFA), derived from Withania
somnifera, is a promising drug candidate for neutrophilic asthma. WFA has beneficial effects in models of other
respiratory diseases, and we have shown that WFA directly inhibits neutrophilic inflammation in vitro and
mitigates airway neutrophilia in a neutrophilic asthma mouse model. However, therapeutic mechanism(s) of WFA
are not well understood, and continued research is needed to elucidate cellular processes impacted by WFA.
The research objective of this K01 is to investigate the mechanisms that underlie therapeutic effects of WFA
for neutrophilic asthma, utilizing advanced 3D in vitro systems to model key steps in neutrophil recruitment, co-
culture to model processes that are central to inflammation resolution, and a published mouse model of
neutrophilic asthma to evaluate these processes in vivo. In Aim 1, we will establish the effect of WFA on
neutrophil migration across lung endothelium and airway epithelium using microfluidic devices and air-liquid
interface culture, respectively. In Aim 2, we will determine the effect of WFA on neutrophil efferocytosis by
alveolar macrophages and on alveolar macrophage phenotype. In Aim 3, we will investigate whether WFA
mitigation of airway inflammation in a mouse model of neutrophilic asthma is mediated by decreased neutrophil
recruitment to the airway and/or increased neutrophil clearance from the airway. Successful comp
Istituzione: NORTH CAROLINA STATE UNIVERSITY RALEIGH
PI: Rosemary L Bayless
Progetto: 1K01OD039838-01A1
Settori: NIH Office of the Director
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