Hyperoxia exposure in an aging model of type 1 diabetes

1 型糖尿病衰老模型中的高氧暴露

• 批准号: 9977485
• 负责人: Siva Kumar Panguluri
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977485
• 关键词: Acute Lung Injury; Acute respiratory failure; Admission activity; Age; Aging; American; Animal Model; Arrhythmia; Biochemical; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Cells; Cerebrum; Cessation of life; Complication; Congestive Heart Failure; Coronary; Critical Care; Critical Illness; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Echocardiography; Elderly; Electrocardiogram; Electrophysiology (science); Female; Functional disorder; Gender; Goals; Health Care Costs; Health Personnel; Heart; Heart Rate; Hospital Mortality; Hyperoxia; Hypoxia; Incidence; Insulin-Dependent Diabetes Mellitus; Investigation; Kidney; Kv channel-interacting protein 2; Left Ventricular Hypertrophy; Left ventricular structure; Life; Life Expectancy; Mechanics; Methods; Modeling; Molecular; Molecular Analysis; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxygen; Oxygen Therapy Care; Patch-Clamp Techniques; Patients; Physiological; Population; Predisposition; Publishing; Regulation; Reporting; Respiratory physiology; Risk; Risk Factors; Sex Differences; System; Ventricular Remodeling; Wild Type Mouse; Woman; age related; aged; base; cardiovascular disorder risk; cardiovascular risk factor; comorbidity; constriction; coronary fibrosis; diabetic patient; differential expression; epidemiology study; experimental study; high risk; insight; male; men; mortality; mortality risk; non-diabetic; novel; older patient; patch clamp; prevent; response; targeted treatment; ventilation

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.

项目概要： ICU中的患者常规给予高水平的氧气以治疗急性肺损伤中的缺氧。 损伤、充血性心力衰竭、心脏纤维化和其它危重疾病。然而，高氧处理 （约95%）还导致高氧和随后的冠状动脉、脑血管和肾血管收缩。 据报道，高氧患者的死亡率较高。糖尿病是最常见的共病之一， ICU患者的条件，他们接受高氧通气。美国糖尿病协会 (ADA)据估计，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T1D患者的一个主要问题。 患者和医疗保健提供者一样，是T1D死亡的主要原因。患有T1D的男性 3.6-患心血管疾病的风险比非糖尿病患者高10倍，而女性患心血管疾病的风险比非糖尿病患者高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 重构和电重构在高氧处理的T1D雄性和雌性小鼠中，使用功能， 分子和生物化学方法。此外，我们还将调查年轻人和 老龄T1D（秋田）小鼠。我们将进一步确定T1D年轻人和老年人的生理变化 心脏，由于高氧，使用全细胞膜片钳技术。我们最近的调查显示 Kv4.2、KChIP2和Kv1.5的调节可能是高氧诱导的肺纤维化病理生理的主要原因 心中因此，我们预期Kv通道失调是T1D高氧诱导的电重构的基础 小鼠心脏，包括心律失常和复极缺陷的发展。总的来说，这项建议将有助于 为了进一步了解心室肌细胞的物理、分子和生化变化， 在T1D中高氧条件下的重构和电重构。因此，我们的建议至关重要， T1D高氧暴露的疾病发展和进展，而且还需要开发针对T1D的靶向治疗。 重症监护环境中的T1D。