Role of Diabetes-Induced REDD1 in Heart Disease

糖尿病诱导的 REDD1 在心脏病中的作用

基本信息

批准号：
10753497
负责人：
Shaunaci Stevens
金额：
$ 3.44万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753497
关键词：
Ablation Acute-Phase Proteins Address Adult Antioxidants Attenuated Biological Models Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Line Cell physiology Complex Consumption DNA Damage Data Defect Development Diabetes Mellitus Diabetic mouse Diet Disease Dyslipidemias Echocardiography Event Exposure to FRAP1 gene Failure Fatty acid glycerol esters Fellowship Functional disorder Gene Chips Genetic Transcription Guanine Nucleotide Exchange Factors Heart Heart Abnormalities Heart Diseases Heart failure Hypoxia Impairment Infarction Inflammation Inflammatory Inflammatory Response Innovative Therapy Intervention Ischemia Knockout Mice Laboratories Learning Lipids Macrophage Medicine Metabolic Diseases Modeling Molecular Molecular and Cellular Biology Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial dysfunction NF-kappa B Obese Mice Obesity Open Reading Frames Outcome Oxidative Stress Oxidative Stress Induction Palmitates Pathogenesis Pathologic Patients Phosphorylation Phosphotransferases Play Production Protein Biosynthesis Proteins Protocols documentation Reperfusion Therapy Repression Retina Role Saturated Fatty Acids Signal Transduction Stress Stress-Induced Protein Sucrose Systems Analysis Technical Expertise Testing Therapeutic Therapeutic Intervention Training Transgenic Mice Up-Regulation Ventricular Wild Type Mouse biological adaptation to stress chemokine college combat cytokine db/db mouse design endoplasmic reticulum stress gene product glycogen synthase kinase 3 beta heart function inhibitor insight mRNA Translation mortality novel nuclear factor-erythroid 2 prevent preventive intervention protein expression protein kinase R response sensor skills training opportunity transcription factor western diet

项目摘要

Project Summary Heart failure is a leading cause of mortality and morbidity in patients with diabetes and obesity, yet much remains unknown regarding the molecular events whereby metabolic disease causes myocardial dysfunction. At the cellular level, oxidative stress and inflammation are considered hallmarks of myocardial impairment. The overarching hypothesis for this F31 fellowship proposal is that the stress response protein regulated in development and DNA damage 1 (REDD1) plays a maladaptive role in the pathogenesis of heart disease by augmenting the development of oxidative stress and inflammation in cardiomyocytes. Preliminary data support that REDD1 expression is enhanced in the heart of mice fed a Western (i.e., high fat, high sucrose) diet and in cardiomyocyte cultures exposed to the saturated fatty acid palmitate. Recent studies from our laboratory demonstrate a key role for REDD1 in the development of diabetes-induced oxidative stress. More specifically, REDD1 acts via a GSK-3β-dependent signaling axis to suppress the nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant response in the retina of diabetic mice. Additionally, REDD1 was found to promote inflammatory signaling in macrophages by direct sequestration of inhibitor of κB (IκB), leading to nuclear factor kappa B (NF-κB) activation. A role for REDD1 in activation of these two non-conventional signaling axes for Nrf2 repression and NF-κB activation has never been interrogated in the heart. Nor is it know if REDD1 contributes to the development of cardiac dysfunction. To test the hypothesis, I will pursue an experimental protocol involving model systems ranging from intact mice to cardiomyocyte cell cultures. Aim 1 will investigate the mechanism whereby consumption of a Western diet promotes transcriptional upregulation of REDD1 in the heart. Aim 2 will investigate the role of REDD1 in the development of oxidative stress and inflammation in cardiomyocytes. Aim 3 will determine the impact of REDD1 deletion on the development of cardiac dysfunction. In addition to my continued graduate training in molecular biology and cellular physiology at Penn State College of Medicine, this fellowship will provide key training opportunities with experts in cardiovascular dysfunction. Specifically, I will learn to properly culture and manipulate adult ventricular cardiomyocytes and develop the technical expertise in echocardiography to assess the impact of REDD1 on cardiac function in transgenic mice. With respect to outcomes, the project will not only expand my skills and systems of analysis beyond those of my primary Sponsor, but will also potentially identify and characterize a unifying regulatory mechanism whereby metabolic disease limits the endogenous antioxidant response and upregulates inflammation in heart. Identification of such a mechanism is significant because it will validate new targets for the development of preventative and/or therapeutic interventions aimed at addressing the molecular basis of heart failure.

项目概要心力衰竭是糖尿病和肥胖患者死亡和发病的主要原因，但仍有许多问题关于代谢疾病导致心肌功能障碍的分子事件尚不清楚。细胞水平、氧化应激和炎症被认为是心肌损伤的标志。该 F31 奖学金提案的总体假设是应激反应蛋白在发育和 DNA 损伤 1 (REDD1) 在心脏病的发病机制中发挥着适应不良的作用增强心肌细胞氧化应激和炎症的发展。 REDD1 表达在喂食西方（即高脂肪、高蔗糖）饮食的小鼠心脏中增强，并且在我们实验室最近对暴露于饱和脂肪酸棕榈酸酯的心肌细胞培养物进行了研究。证明 REDD1 在糖尿病引起的氧化应激的发展中发挥关键作用。 REDD1 通过 GSK-3β 依赖性信号轴发挥作用，抑制核因子 erythroid-2 相关因子 2 此外，REDD1 还被发现可以促进糖尿病小鼠视网膜中的 (Nrf2) 抗氧化反应。通过直接隔离 κB (IκB) 抑制剂，导致巨噬细胞中的炎症信号转导产生核因子 kappa B (NF-κB) 激活。REDD1 在 Nrf2 的这两个非常规信号轴激活中的作用。心脏中的抑制和 NF-κB 激活从未被研究过，也不知道 REDD1 是否起作用。为了检验这个假设，我将采用一个涉及心脏功能障碍的实验方案。从完整小鼠到心肌细胞培养物的模型系统将研究其机制。食用西方饮食会促进心脏中 REDD1 的转录上调。研究 REDD1 在心肌细胞氧化应激和炎症发展中的作用。 3 将确定 REDD1 缺失对心功能障碍发展的影响。在宾夕法尼亚州立大学医学院继续分子生物学和细胞生理学研究生培训，这奖学金将为心血管功能障碍专家提供重要的培训机会。学习正确培养和操作成人心室心肌细胞并发展以下方面的技术专长超声心动图评估 REDD1 对转基因小鼠心脏功能的影响。结果，该项目不仅将扩展我的技能和分析系统，超出我的主要能力发起人，但也有可能确定和表征一个统一的监管机制，通过该机制代谢疾病限制了内源性抗氧化反应并上调了心脏中的炎症。机制很重要，因为它将验证制定预防性和/或旨在解决心力衰竭的分子基础的治疗干预措施。