MECHANISMS OF ANESTHETIC CARDIOPROTECTION

麻醉心脏保护机制

• 批准号: 8793576
• 负责人: Zeljko J. Bosnjak
• 金额: $ 178.38万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793576
• 关键词: Acute; Address; Affect; Anatomy; Anesthesiology; Anesthetics; Animal Model; Animals; Biochemistry; Bioenergetics; Biomedical Engineering; Biophysics; Biotechnology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Cellular biology; Collaborations; Computer Simulation; Data; Defect; Derivation procedure; Development; Diabetes Mellitus; Diabetic mouse; Disease; Doctor of Philosophy; Electrophysiology (science); Ensure; Environmental Risk Factor; Fibroblasts; Future; Gene Expression; Goals; Heart; Homeostasis; Human; Human Genetics; In Vitro; Individual; Injury; Investigation; Isoflurane; Knock-out; Knockout Mice; Lead; Link; Maintenance; Measures; Mediating; Medicine; MicroRNAs; Mitochondria; Modeling; Molecular; Molecular Genetics; Monitor; Neurobiology; Non-Insulin-Dependent Diabetes Mellitus; Patients; Pharmacology; Phenotype; Physiology; Pluripotent Stem Cells; Predisposition; Preparation; Proteins; Rattus; Recording of previous events; Reperfusion Injury; Research; Research Infrastructure; Research Personnel; Role; Sendai virus; Services; Signal Pathway; Signal Transduction; Skin; Stem cells; Stress; Systems Biology; Testing; Time; Toxic effect; Translating; Wisconsin; Work; base; cell growth regulation; design; diabetic; diabetic patient; diabetic rat; genome integrity; human disease; in vivo; induced pluripotent stem cell; insight; medical schools; meetings; non-diabetic; novel; overexpression; pluripotency; programs; public health relevance; research study; translational approach

 DESCRIPTION (provided by applicant): The central theme of our PPG is to gain fundamental insight into the mechanisms responsible for greater susceptibility of diabetic hearts to ischemia-reperfusion injury using both patient-derived cardiomyocytes and diabetic animals. We will use anesthetics to test the ability of diabetic animals and human cardiomyocytes to be protected against ischemia-reperfusion injury for the future development of novel cardioprotective strategies for the diabetic heart. Our hypothesis is that diabetes undermines cardioprotection through actions on cardiomyocytes that are both environmental and cellular in origin. Our translational approach will include in vivo diabetic animal models, isolated animal heart preparations, isolated animal cardiomyocytes and mitochondria, computer simulations and modeling of mitochondrial and cellular function in anesthetic cardioprotection, and finally, human cardiomyocytes derived from disease-specific induced pluripotent stem cells (iPSC). The following closely interrelated and interdependent Projects will address different facets of this theme: Project I (PI: Zeljko J. Bosnjak - Anesthesiology) will utilize human cardiomyocytes derived from the iPSC obtained from non-diabetic individuals and patients with type 2 diabetes mellitus along with a rat model of type 2 diabetes developed at the Medical College of Wisconsin (T2DNmtFHH or T2DN for short). Our fundamental hypothesis is that diabetes and glucolipotoxicity impair anesthetic cardioprotection through signaling components that can be favorably modulated to restore anesthetic cardioprotection during diabetes. Project II (PI: Mingyu Liang - Physiology) will examine the role of miR-21 in anesthetic cardioprotection in non-diabetic and diabetic mice and rats, translate the findings to human using patient-specific cardiomyocytes, and investigate the molecular mechanisms involved. This project will test the hypothesis that a change of miR- 21 expression will restore isoflurane-conferred protection in diabetic animal models and in patient-specific cardiomyocytes. Project III (PI: Ranjan K. Dash - Biotechnology and Bioengineering Center and Physiology) will use a system biology approach to iteratively conduct experiments and use the measured data to computationally model and mechanistically characterize the specific effects and associated mechanisms of volatile anesthetic action on mitochondrial and cellular function that lead to cardioprotection, and how diabetic conditions impair this protection. Administrative Core (Director: Zeljko J. Bosnjak - Anesthesiology) will provide an organized and comprehensive framework of support for all subprojects and cores contributing to the cohesive functionality of the Program while ensuring regulatory compliance. Stem Cell Core (Director: Stephen A. Duncan - Cell Biology, Neurobiology and Anatomy) will support all projects by supplying patient-derived iPSC lines and differentiate these cells into disease-specific cardiomyocytes. Thus, all three Projects focus cohesively on the role of diabetes undermining the cardioprotection. This is a highly focused Program that will be led by investigators who have worked together for many years, and their history of collaboration has resulted in closely linked individual Projects that are ideally suitedfor the continuation of this PPG. These investigations will be supported by well-established state-of-the-art facilities in Anesthesiology Research, and the Departments of Physiology; Biophysics; Biochemistry; Pharmacology; Cell Biology, Neurobiology and Anatomy; Medicine; Cardiovascular Research Center; Human and Molecular Genetic Center and Biotechnology and Bioengineering Center.

 描述（由适用提供）：我们的PPG的中心主题是获得对使用患者衍生的心肌细胞和糖尿病动物对糖尿病心脏对缺血 - 再灌注损伤的敏感性更大的机制的基本见解。我们将使用麻醉药来测试糖尿病动物和人类心肌细胞的能力，以防止糖尿病心脏的新型心肌细胞的未来发育，以防止缺血 - 再灌注损伤。我们的假设是，糖尿病通过对既是环境和原始细胞的心肌细胞的作用降低心脏保护作用。我们的翻译方法将包括体内糖尿病动物模型，孤立的动物心脏制剂，孤立的动物心肌细胞和线粒体，计算机模拟以及麻醉性心脏保护作用中线粒体和细胞功能的建模，最后是源自疾病疾病诱导的pluripotent pluroipotent细胞（IPSC）。以下紧密相互关联和相互依存的项目将解决该主题的不同方面：项目I（PI：Zeljko J. Bosnjak - 麻醉学 - 麻醉学）将利用人类心肌细胞从非糖尿病患者和2型糖尿病患者以及2型糖尿病的型糖尿病的患者以及在2型糖尿病中获得的患者获得的人类心肌细胞（Typiin type 2 diabeters of 2 diabets typer）或简称T2DN）。我们的基本假设是，糖尿病和葡萄糖毒素通过信号传导成分损害麻醉性心脏保护作用，这些成分可以在糖尿病期间受到有利调节以恢复麻醉性心脏保护作用。项目II（PI：Mingyu Liang-生理学）将检查miR-21在非糖尿病和糖尿病小鼠和大鼠麻醉性心脏保护中的作用，并使用患者特异性心肌细胞将发现转化为人，并研究涉及的分子机制。该项目将检验以下假设：MiR-21表达的变化将恢复糖尿病动物模型和患者特异性心肌细胞中的异氟烷限制的保护。项目III（PI：Ranjan K. Dash-生物技术和生物工程中心和生理学）将使用系统生物学方法进行迭代进行实验，并使用测量的数据来计算模型，并在机械上表征了对线粒体和蜂窝细胞功能的挥发性麻醉作用的特定效果和相关机制，并影响了cardi cartiair to cardi cardi cardi cardi cardi cardi cardi＆cardioprotection＆cardi cardiorpotect。行政核心（主任：Zeljko J. Bosnjak - 麻醉学）将为所有有助于该计划的凝聚力功能的副本和核心提供有组织而全面的支持框架，同时确保监管合规性。干细胞核心（主管：Stephen A. Duncan-细胞生物学，神经生物学和解剖学）将通过提供患者衍生的IPSC线并将这些细胞区分为疾病特异性的心肌细胞，来支持所有项目。这是一个非常注重的计划，将由研究人员领导，他们合作了多年，他们的协作历史已经导致了密切相关的个体项目，这些项目非常适合继续该PPG。这些调查将得到麻醉研究和生理学部门的完善的最新设施；生物物理学；生物化学；药理;细胞生物学，神经生物学和解剖学；药品;心血管研究中心；人类和分子遗传中心以及生物技术和生物工程中心。