Hyperoxia exposure in an aging model of type 1 diabetes

项目总结： ICU中的患者常规给予高氧治疗急性肺缺氧。 受伤、充血性心力衰竭、心脏纤维化和其他危重疾病。然而，高氧处理 (95%)还会导致高氧和随后的冠状动脉、大脑和肾脏血管收缩。 据报道，高氧血症患者的死亡率很高。糖尿病是最常见的并发症之一。 ICU患者的情况，他们接受高氧呼吸。美国糖尿病协会 美国食品药品监督管理局(Ada)估计，目前约有125万美国人患有1型糖尿病 (T1D)。心血管疾病(CVD)是T1D的一种众所周知的并发症，是 患者和医疗保健提供者一样，也是T1D死亡的主要原因。患有T1D的男性处于 患心血管疾病的风险是非糖尿病患者的3.6倍，而女性患心血管疾病的风险是非糖尿病患者的7.7倍 非糖尿病患者。到目前为止，还没有研究确定男性和女性的心血管风险 在一项老龄化研究中，接受高氧暴露的T1D患者。在这项研究中，我们将研究心脏 高氧处理T1D雄性和雌性小鼠的重构和电重构，使用功能性， 分子和生化方法。此外，我们将调查青少年和青少年的高氧暴露。 老年T1D(秋田)小鼠。我们将进一步确定T1D青年和老年发生的生理变化 心脏，由于高氧，采用全细胞膜片钳技术。我们最近的调查表明 Kv4.2、KChIP2和Kv1.5的调控可能是高氧性脑损伤的主要病理生理机制。 红心。因此，我们认为Kv通道失调是高氧诱导的T1D电重构的基础。 小鼠心脏的发育包括心律失常和复极缺陷。总体而言，这项建议将有所帮助 为了进一步加深我们目前对心脏的物理、分子和生化变化的了解 高氧状态下T1D的重构和电重构。因此，我们的建议对于澄清 T1D高氧暴露的疾病发展和进展，但也开发靶向治疗 重症监护环境中的T1D。

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.