PROJECT SUMMARY Puerto Rico, a United States (U.S.) territory, has the highest asthma rates globally, with 14.2 percent of its residents affected at some point. They are more likely to be hospitalized and four times more likely to die from severe asthma compared to any other group in the U.S. Asthma affects 334 million people worldwide, including 7 million children, and is a heterogenous obstructive airway disease, with severe cases accounting for over 50% of its healthcare costs. Severe asthma is characterized by high levels of neutrophil infiltration leading to airway inflammation. The persistent gaps in understanding the immune responses and molecular networks contributing to severe asthma hinder the development of innovative and effective treatments. Usually, cellular inflammation of the airways is driven by eosinophils or neutrophils. The study focus is the neutrophilic asthma subgroup, which accounts for 20 – 30% of all cases. It is characterized by severe and persistent disease, frequent exacerbations, and hospitalizations. Neutrophils play a crucial role in innate immune responses and inflammation through phagocytosis, degranulation, the release of reactive oxygen species, and the release of neutrophil extracellular traps (NETs). Excessive NETs production without an infection leads to inflammation, cellular damage, and organ failure. NETs formation has emerged as a crucial mechanism contributing to asthma pathogenesis via different mechanisms. Thus, supporting the premise that targeting NETs production is a feasible therapeutic target for severe asthma. Spleen Tyrosine Kinase (SYK) is essential for neutrophil activation and the production of NETs. In neutrophilic animal models, SYK inhibition has improved outcomes and reduced airway inflammation. Intriguingly, SYK has been shown to play a role in NETs release and to promote better outcomes in animal models. The central hypothesis is that SYK signaling mediates NETs formation in severe asthma, contributing to the disease’s pathogenesis. The proposed project is of utmost importance as it addresses a pressing and relevant issue in asthma. By characterizing unique populations and conducting functional assays on primary human neutrophils, we will gain new insights into the underlying mechanisms driving severe asthma. The translational relevance of this study is that it will convey fundamental knowledge from human samples to support future clinical trials examining SYK inhibition to complement and improve current asthma management. The research program is based at the highly regarded Ponce Health Sciences University, a Puerto Rican academic institution with a strong clinical research platform focused on addressing health disparities. The principal will be led by two foremost experts in the field. Principal investigators of this study, Marcos J. Ramos-Benitez, PhD, and Wilfredo De Jesús-Rojas, MD, FAAP, MSc, are experts renowned for their expertise in neutrophil biology and clinical and translat...