Dr. Zhang’s current research focuses on identifying the susceptibility genes of ventilator-induced lung injury via an unbiased genome-wide association study (GWAS) in inbred mice and to evaluate its relevant functional significance. Mechanical ventilation (MV) is a valued palliative therapy for the management of a variety of critically ill patients. Nonetheless, this therapy may produce an iatrogenic condition referred to as ventilator-induced lung injury (VILI). Sensitivity to VILI varies greatly in patient subpopulations, suggesting that genetic determinants may control individual susceptibility. Although much effort and progress has been made over past 40 years, the underlying mechanisms behind MV and its cellular responses that result in VILI remain unclear. MV is an important risk factor in the pathogenesis of ALI. High tidal volume VILI animal models have exhibited increased alveolar-capillary permeability, inflammation leading to pulmonary edema, and diffuse alveolar damage that closely mimics the pathologic aspects of ALI; therefore, the VILI animal model is a realistic tool to explore the underlying mechanisms for ALI. Using an unbiased GWAS of a genetically diverse panel of 23 mouse strains, we recently identified a stretch inducible molecule and a Wnt/β-catenin signaling pathway target gene, WNT1 inducible signaling pathway protein 1 (WISP1) in a murine model of VILI. We found that WISP1 protein level increased in the lung and bronchoalveolar lavage fluid after VILI and that anti-WISP1 antibody decreased lung injury, whereas intratracheal administration of recombinant WISP1 protein increased lung permeability in VILI. Moreover, we have discovered that the innate immune signaling via TLR4 plays a critical role in the pathogenesis of VILI and that the stretch-induced WISP1 expression and its pro-inflammatory effects are TLR4-dependent. Successful completion of this study could yield novel insights that could lead to a diagnostic (e.g. biomarker) and/or therapeutic target for future translation in humans.