ABSTRACT Asthma is a heterogeneous and highly burdensome disease that is concentrated in communities of color and of low socioeconomic status. Clinical asthma heterogeneity reflects complex interactions between molecular, environmental, and social factors that combine to influence disease outcomes and therapeutic response. Socio- environmental exposures, including psychosocial stressors and air pollution, are concentrated in historically marginalized communities where they contribute to poor asthma outcomes. However, the mechanisms underlying these exposure-related outcomes are poorly understood. There is a critical need to understand how asthma molecular heterogeneity 1) operates in marginalized populations; and, 2) is influenced by prevalent socio-environmental factors. The proposed multi-omics approach considering pathology both systemically and at the main site of disease, the airways, is crucial to unraveling the complex interactions between exposures, mechanisms, and outcomes in these understudied communities. This project aims to enroll 200 youth with and 100 youth without asthma in Richmond, CA, a predominantly Latine community with high socio-environmental stressor burden and asthma prevalence upwards of 25%. Multi-omic data will be derived from blood and airway (nasal swab and sputum) samples collected at disease stability over one year and airway samples collected during acute respiratory events and recovery. These data will be integrated with deep phenotyping and exposure data to test three specific aims. The first aim will examine the relationships between high psychosocial stress and multi-omic outcomes across asthma and health. A hypothesis driven approach will focus on stress- associated asthma-relevant pathologic alterations including systemic and airway immune responses, stress hormone associated microbiome shifts, and beta-adrenergic and glucocorticoid pathology. The second aim will examine the relationships between indoor and outdoor air pollution and multi-omic outcomes across asthma and health. Indoor and fine-resolution outdoor air pollution monitoring will be leveraged for exposure assessments to consider how pollutants relate to immune responses, airway repair, and cellular stress across multi-omic layers. The third aim will examine the role of socio-environmental and microbial precipitants in asthma exacerbation susceptibility and mechanisms, leveraging samples obtained at baseline and during acute respiratory events. A custom multi-omic analytical pipeline that considers microbial exacerbation precipitants along with environmental exposures will be used. Our ultimate goal is to understand the mechanisms underlying socio-environmental exposures that influence asthma outcomes to inform therapeutic and management decisions and influence targets for place-based mitigation efforts.