PKA Signaling and Metabolic Inflexibility in the Diabetic Heart

糖尿病心脏中的 PKA 信号传导和代谢不灵活

基本信息

批准号：
9306179
负责人：
Kenneth M Humphries
金额：
$ 42.88万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306179
关键词：
Address Adenoviruses Adrenergic Agents Adult Affect Area Arrhythmia Autophagocytosis Bioenergetics Biological Assay Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Catecholamines Cell Nucleus Cyclic AMP-Dependent Protein Kinases Cytoplasm Cytosol Defect Diabetes Mellitus Diabetic mouse Enzymes Foundations Fructose Functional disorder Genus Hippocampus Glucose Goals Heart Heart Diseases Heart failure Hyperglycemia Hyperlipidemia Impairment Incidence Insulin Insulin-Dependent Diabetes Mellitus Knowledge Learning Life Measures Mediating Metabolic Metabolism Molecular Mus Myocardial dysfunction Nature Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Family Nuclear Protein PKA inhibitor Pathway interactions Pharmacology Phosphorylation Phosphotransferases Play Population Positioning Attribute Prevention Process Production Protein Family Protein Isoforms Protein Kinase Protein Kinase Inhibitors Proteins Receptor Signaling Recycling Regulation Risk Factors Role Scheme Severities Signal Pathway Signal Transduction Stress Testing Therapeutic Intervention Work Workload base beta-adrenergic receptor biological adaptation to stress desensitization diabetic diabetic cardiomyopathy experimental study falls flexibility heart metabolism mouse model multicatalytic endopeptidase complex oxidation prevent protein activation protein kinase inhibitor public health relevance receptor small hairpin RNA therapeutic target type I diabetic

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this project is to understand how diabetes affects the heart and derive better treatment options. This is especially important given the high incidence of diabetes and ensuing cardiovascular complications. Indeed, diabetes can induce changes to cardiac function in the absence of other risk factors through mechanisms that are not completely clear. The focus of this proposal is to understand how the beta-adrenergic signaling pathway is affected by diabetes, and how these changes may exacerbate and enhance stress on the heart. Activation of cAMP-dependent protein kinase (PKA) via beta-adrenergic receptor signaling is a primary means of increasing cardiac contractility. Over- activation or dysregulation of this pathway is a major driver of diabetic cardiomyopathy, life threatening arrhythmias, and heart failure. However, the mechanisms by which this pathway becomes disrupted are largely unknown. In the healthy heart, PKA increases contractility by amplifying calcium cycling and concertedly activates phosphor-fructose kinase-2 (PFK-2) to promote glucose oxidation. In this manner, workload and metabolic demand are finely orchestrated. The studies of this application address how this orchestration becomes disrupted. The foundation for this work is based on our recent discovery that in the diabetic heart PFK-2 is unresponsive to direct PKA activation, suggesting that post-receptor signaling is compromised. Moreover, our results indicate that this unresponsiveness of PFK-2 is mediated by a decrease in PKA inhibitors (PKIs), a family of nuclear proteins that inhibit PKA and facilitate its transport to the cytoplasm. These findings have led to our overarching hypothesis that diabetes-induces a deficiency of PKI, resulting in aberrant localization and activity of PKA that abrogates PFK2 activation and promotes cardiomyopathy. This hypothesis is being tested and explored using murine models of diabetes and adult primary cardiomyocytes. In Aim 1, we are examining how PKA signaling differs in the diabetic heart and how this changes in cardiac function. Mechanistic studies are being performed to understand how diabetic metabolic conditions mediate these changes. In Aim 2, we are defining the cause and consequence of decreased PKI levels. This aim builds off our recent discovery of the dynamic nature of these proteins. In Aim 3, we are testing the hypothesis that PFK-2 plays an essential role in maintaining metabolic flexibility following beta-adrenergic stimulation. We are defining how PFK-2 levels are affected by diabetes and how this desensitizes this enzyme to PKA activation. These studies will investigate a completely unexplored but critical area of PKA regulation and signaling and how they are impacted by, and perhaps contribute to, diabetic cardiac dysfunction. Results from this study may aid in developing therapeutic targets downstream of beta-receptors.

描述（由申请人提供）：该项目的长期目标是了解糖尿病如何影响心脏并得出更好的治疗方案，鉴于糖尿病和随之而来的心血管并发症的高发病率，这一点尤其重要。该提案的重点是了解糖尿病如何影响β-肾上腺素能信号通路，以及这些变化如何加剧和增强心脏的压力。激活cAMP 依赖性蛋白激酶 (PKA) 通过 β 肾上腺素能受体信号传导是增加心脏收缩力的主要手段，该途径的过度激活或失调是糖尿病性心肌病、危及生命的心律失常和心力衰竭的主要驱动因素。在健康心脏中，PKA 通过放大钙循环并协同激活磷酸果糖激酶 2 (PFK-2) 来增加收缩力，但该途径被破坏的机制很大程度上尚不清楚。通过这种方式，工作量和代谢需求得到精心安排。这项研究的基础是我们最近发现 PFK-2 在糖尿病心脏中没有反应。指导 PKA 激活，表明受体后信号转导受到损害。此外，我们的结果表明 PFK-2 的这种无反应是由 PKA 抑制剂的减少介导的。（PKIs），一个抑制 PKA 并促进其转运到细胞质的核蛋白家族，这些发现导致了我们的总体假设：糖尿病诱导 PKI 缺陷，导致 PKA 的异常定位和活性，从而消除 PFK2 激活和正在使用糖尿病小鼠模型和成人原代心肌细胞对该假设进行测试和探索。在目标 1 中，我们正在研究 PKA 信号传导在糖尿病心脏中的差异。正在进行机制研究，以了解糖尿病代谢状况如何介导这些变化。在目标 2 中，我们正在定义 PKI 水平下降的原因和后果。在目标 3 中，我们正在测试 PFK-2 在维持 β-肾上腺素能刺激后的代谢灵活性方面发挥重要作用的假设，我们正在定义 PFK-2 水平如何受到糖尿病的影响以及这如何使其变得不敏感。这些研究将研究 PKA 调节和信号传导的一个完全未被探索但关键的领域，以及它们如何受到糖尿病心脏功能障碍的影响，并可能有助于开发糖尿病心脏功能障碍的下游治疗靶点。 β-受体。