Project Summary: Patients in the ICU are routinely administered high levels of oxygen for the treatment of hypoxia in acute lung injury, congestive heart failure, cardiac fibrosis, and in other critical illness. However, high oxygen treatment (?95%) also results in hyperoxia and subsequent constriction of the coronary, cerebral, and renal vasculatures. High mortality has been reported in patients with hyperoxia. Diabetes is one of the most common comorbid conditions in ICU patients, who undergo ventilation with high oxygen. The American Diabetes Association (ADA) estimates that there are approximately 1.25 million Americans currently living with type 1 diabetes (T1D). Cardiovascular disease (CVD) is a well-known complication of T1D and represents a major concern for patients and healthcare providers alike and are the leading cause of mortality in T1D. Men with T1D are at a 3.6-fold higher risk for CVD than nondiabetics, while women are at a 7.7-fold higher risk of CVD than nondiabetics. To date, there have been no studies that establish the cardiovascular risk of male and female T1D patients, who undergo hyperoxia exposure, in an aging study. In this study, we will investigate cardiac remodeling and electrical remodeling in hyperoxia-treated T1D male and female mice, using functional, molecular, and biochemical methods. Additionally, we will investigate hyperoxia exposures in both young and old T1D (Akita) mice. We will further determine physiological changes which occur in T1D young and old hearts, as a result of hyperoxia, using whole-cell patch-clamping technique. Our recent investigations suggest that regulation of Kv4.2, KChIP2 and Kv1.5 may be the major cause for pathophysiology of hyperoxia- induced hearts. Thus, we expect Kv channel dysregulation to underlie hyperoxia-induced electrical remodeling in T1D mouse hearts, including development of arrhythmias and defects repolarization. Overall, this proposal will help to further our current understanding of the physical, molecular and biochemical changes regarding ventricular remodeling and electrical remodeling in hyperoxia conditions in T1D. Thus, our proposal is crucial to clarify disease development and progression in hyperoxia exposure in T1D, but also to develop targeted therapy for T1D in critical care settings.