Summary/Abstract Airway wall remodeling is one of the most documented hallmarks of asthma. Despite being a key clinical trait of long-term asthma, this pathological condition remains largely uncontrolled even with front-line therapies. Remodeling processes have been traditionally described as an aberrant response to chronic inflammation. However, this picture is challenged by increasing evidence of airway remodeling as a primary mechanotransduction event. Recent studies point to mechanical abnormalities in the airway epithelium as a core factor of asthma pathogenesis. In vitro and in vivo experiments show that the mechanical effects of asthmatic bronchoconstriction can trigger alone genomic, molecular, and morphological patterns of airway remodeling even in the absence of inflammatory stimuli. As such, the traditional picture of asthma as a predominantly inflammatory disease is giving way to a complex, multifactorial scenario where mechanical forces, immune response, and tissue remodeling all contribute to the development of the disease. Building upon these findings, this proposal hypothesizes that the mechanogenetic response of the airway epithelium to excessive mechanical stress constitutes a route to aberrant airway remodeling that is independent of inflammation. To test this hypothesis, Dr. De Marzio will develop a novel systems biology approach that combines genomics, biostatistics, and network medicine. RNA-Sequencing and clinical data from asthma population studies will be integrated with protein interaction networks to: 1) Identify the mechanogenetic signature of bronchoconstriction in the asthmatic epithelium and understand its role on asthmatic phenotypes; 2) define the role of airway epithelial cell heterogeneity in response to mechanical compression; and 3) determine the signaling pathways mediating compression-induced airway remodeling to discover candidate therapeutic markers. In doing so, this project will represent the first comprehensive study on the mechanogenomics of asthma. The intrinsic interdisciplinary nature of this proposal makes Dr. De Marzio uniquely qualified to pursue this research direction. The proposed research will leverage her physics background and her experience in computational biology and network modeling to understand the pathogenic role of mechanical forces in asthma. For the successful development of this project, she will receive additional training in airway pathobiology and pulmonary medicine and she will be supported by an outstanding mentoring team composed of biologists, network scientists, and pulmonologists. Dr. De Marzio's long-term career goal is to establish an independent research program at the intersection of genomics, biomechanics, and network science. The resources offered by this award combined with the rich intellectual environment of the Channing Division of Network Medicine will put her in an advantageous position to transition to independence and submit multiple R01s. Dr. De Marzio's f...