Human Cell and Tissue Acquisition Core

Project Abstract: Translational science provides clinically relevant human model systems to study disease pathogenesis and to identify new therapeutic targets. Leveraging this approach, the overall goal of Core B is to provide standardized and well-characterized human airway smooth muscle (HASM) cell and tissue platforms to explore the molecular mechanisms that modulate HASM contractility, relaxation, and growth in asthma. For all projects, Core B serves as a centralized human cell and tissue resource that will provide primary HASM and human precision cut lung slices (hPCLS) and offer specialized single cell and tissue assays to measure the shortening of HASM, the pivotal cell regulating bronchomotor tone. Three aims are proposed to accomplish the Core B goals. In Aim 1, we will provide state-of-the-art single-cell models of HASM contractility and relaxation (including magnetic twisting cytometry and Fourier transform traction microscopy), enabling investigators to explore excitation- contraction (EC) coupling pathways and identify new therapeutic targets. Findings in HASM cells derived from donors with asthma that retain a phenotype of hyperresponsiveness to contractile agonists and insensitivity to β-agonist will be compared with those derived from age-, sex-, and race-matched non-asthma donors. Aim 2 will examine how these EC signaling pathways in HASM cells translate into an integrated tissue model of the airways using human precision-cut lung slices (hPCLS). Aim 3 will assess the modulation of contractile and relaxant pathways using asthma-relevant exacerbation models, including airway inflammation and allergen-induced airway hyperresponsiveness. Taken together, Core B is integral to the success of the PPG, and our Aims will provide valuable platforms and molecular tools that will serve the needs of the PPG investigators who will address mechanisms underlying bronchoconstriction and bronchodilation in asthma.