BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy

缺血性和非缺血性心肌病中的 BDNF TrkB- 和 beta-AR 信号

• 批准号: 9447993
• 负责人: Nazareno Paolocci
• 金额: $ 59.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-11 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447993
• 关键词: Accounting; Acute; Adrenergic Receptor; Adrenergic alpha-Antagonists; Agonist; Animal Model; Attenuated; Binding; Brain-Derived Neurotrophic Factor; Canis familiaris; Cardiac; Cardiac Myocytes; Cells; Chronic; Clinical; Collaborations; Coupled; Data; Dilated Cardiomyopathy; Down-Regulation; Etiology; Fostering; Functional disorder; G protein coupled receptor kinase; Generations; Goals; Heart; Heart Arrest; Heart Diseases; Heart failure; Human; Impairment; Infusion procedures; Injury; Knock-out; Knockout Mice; Left; Left ventricular structure; Metabolic; Metabolism; Metoprolol; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pathologic; Peptides; Phosphotransferases; Physiological; Prevention; Production; Proteins; Relaxation; Research; Signal Transduction; Stress; Symptoms; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; Tropomyosin; Up-Regulation; Ventricular; clinically relevant; desensitization; design; functional outcomes; hemodynamics; improved; inhibitor/antagonist; novel; overexpression; pre-clinical; prevent; receptor; research clinical testing; sphingosine 1-phosphate; therapeutic target

Brain-derived neurotrophic factor (BDNF) and its associated, specific tropomyosin related kinase B (TrkB) receptor modulates basal myocardial function and low circulating BDNF levels correlate with worsening of symptoms in heart failure (HF) subjects. Deleting BDNF in myocytes leads to prominent LV dilation at baseline, but basal and stress-stimulated left ventricle (LV) function was never tested in cBDNF-/- mice. Our pilot data suggest that left ventricles from human and experimental HF subjects are massively BDNF depleted. Despite this experimental and clinical evidence, cardiac BDNF/TrkB remains largely understudied. The long-term goal is to determine factors accounting for loss in BDNF/TrkB signal in failing hearts, and mechanisms whereby re- introducing BDNF via TrkB stimulation in BDNF-depleted failing hearts affords protection against ischemic and non-ischemic stress. Here we advance the following three novel hypotheses: 1) that myocardial BDNF generation prevents chronic cardiac decompensation in infarcted hearts, and proper βAR activity is involved in this generation; 2) that direct S1PRs stimulation enhances myocardial BDNF production, preventing LV decompensation in infarcted mice, and that selective β1AR-blockers rescue β3AR down-regulation in post-MI hearts, increasing myocardial BDNF levels via β3-AR/S1PRs signal; 3) that cardiac TrkB stimulation rescues β-AR sensitivity and improves decompensation in a dog model of non-ischemic cardiomyopathy. The rationale for the proposal is that understanding how loss in BDNF/TrkB signal contributes to myocardial adaptation to ischemic or non-ischemic cardiac stress will advance efforts to therapeutically harness this capacity for clinical relevant conditions associated to loss of cardiomyocytes due to ischemic or non-ischemic cardiac diseases. The central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will determine if deleting myocardial BDNF worsens outcome in mice with myocardial infarction, and to test whether TrkB agonists rescues BDNF expression and β-AR sensitivity in infarcted hearts, the latter by inhibited GRK2, the major kinase liable for cardiac β-AR desensitization. In Aim 2, we will test if direct β3-AR or S1PRs stimulation enhances myocardial BDNF content to protect the myocardium against myocardial infarction; In Aim 3, we will test whether the chronic infusion of TrkB agonists rescues LV function in dogs with tachypacing-induced HF via improved myocardial efficiency and restored β-AR sensitivity. The proposed research is significant, because it is expected to foster our understanding of a novel compensatory mechanism, BDNF/TrkB signal that can enable the heart to preserve functional integrity and energetic efficiency in myocardial cells under condition of ischemic or non-ischemic stress, and to determine whether TrkB agonists merit further consideration for clinical testing in HF.

脑衍生的神经营养因子（BDNF）及其相关的特异性肌球蛋白相关激酶B（TRKB） 受体调节基本的心肌功能和低循环BDNF水平与遗憾相关 心力衰竭（HF）受试者的症状。在肌细胞中删除BDNF会导致基线时突出的LV扩张， 但是在CBDNF - / - 小鼠中从未测试过基本和应力刺激的左心室（LV）功能。我们的飞行员数据 表明来自人类和实验性HF受试者的左心室大大耗尽。尽管 这是实验性和临床证据，心脏BDNF/TRKB仍然在很大程度上被理解。长期目标是 确定因失败心脏中BDNF/TRKB信号损失的因素，以及机制的损失。 通过trkB刺激引入bdnf的bdnf depleded失败的心脏可保护缺血和 非缺血应力。在这里，我们提出以下三个新颖的假设：1）心肌BDNF 产生可防止梗塞心脏中慢性心脏代表性，并且涉及适当的βAR活性 在这一代人中； 2）直接S1PRS模拟增强心肌BDNF的产生，防止LV 梗塞小鼠的代偿作用，并且选择性β1AR阻滞剂挽救了MI后的β3AR下调 心脏，通过β3-AR/S1PRS信号增加心肌BDNF水平； 3）心脏TRKB刺激救援 β-AR敏感性并改善了非缺血性心肌病模型中的代偿作用。 该提案的理由是了解BDNF/TRKB信号中的损失如何有助于心肌 适应缺血性或非缺血性心脏压力将促进治疗能力来利用这种能力 对于临床相关条件，与缺血性或非缺血性心脏有关的心肌细胞丧失 疾病。中心假设将以三个集成的特定目的进行测试。在AIM 1中，我们将确定 如果删除心肌bdnf会使心肌梗塞的小鼠恶化，并测试是否trkb 激动剂反应受感染心脏的BDNF表达和β-AR敏感性，后者通过抑制GRK2， 主要的激酶负责心脏β-AR脱敏。在AIM 2中，我们将测试直接β3-AR还是S1PRS刺激 增强心肌BDNF含量，以保护心肌免受心肌梗塞；在AIM 3中，我们将 测试TRKB激动剂的慢性输注是否反应tachypacing诱导的HF通过 提高心肌效率并恢复了β-AR敏感性。拟议的研究很重要，因为 预计它将促进我们对一种新型补偿机制，BDNF/TRKB信号的理解 使心脏能够在条件下保持心肌细胞的功能完整性和能量效率 缺血性或非缺血性压力，并确定TRKB激动剂是否值得进一步考虑临床 在HF中进行测试。