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.

脑源性神经营养因子 (BDNF) 及其相关的特异性原肌球蛋白相关激酶 B (TrkB) 受体调节基础心肌功能，低循环 BDNF 水平与病情恶化相关 心力衰竭（HF）受试者的症状。删除肌细胞中的 BDNF 会导致基线时左室显着扩张， 但从未在 cBDNF-/- 小鼠中测试过基础和应激刺激的左心室 (LV) 功能。我们的试点数据 表明人类和实验性心力衰竭受试者的左心室大量 BDNF 耗尽。尽管 根据这一实验和临床证据，心脏 BDNF/TrkB 的研究仍处于很大程度上不足。长期目标是 确定导致衰竭心脏中 BDNF/TrkB 信号丢失的因素，以及重新启动的机制 通过 TrkB 刺激在 BDNF 耗尽的衰竭心脏中引入 BDNF，可以防止缺血和 非缺血性应激。在这里，我们提出以下三个新假设：1）心肌 BDNF 生成可防止梗塞心脏中的慢性心脏失代偿，并且涉及适当的 βAR 活性 在这一代； 2) 直接刺激 S1PR 可增强心肌 BDNF 的产生，预防 LV 梗塞小鼠失代偿，选择性 β1AR 阻滞剂可挽救 MI 后 β3AR 下调 心脏，通过 β3-AR/S1PRs 信号增加心肌 BDNF 水平； 3)心脏TrkB刺激挽救 β-AR 敏感性并改善非缺血性心肌病狗模型的失代偿。 该提案的基本原理是了解 BDNF/TrkB 信号的丢失如何影响心肌 对缺血性或非缺血性心脏应激的适应将推动在治疗上利用这种能力的努力 用于与缺血性或非缺血性心脏病引起的心肌细胞损失相关的临床相关病症 疾病。中心假设将在三个综合具体目标中进行检验。在目标 1 中，我们将确定 删除心肌 BDNF 是否会使心肌梗塞小鼠的结果恶化，并测试 TrkB 是否 激动剂可挽救梗塞心脏中的 BDNF 表达和 β-AR 敏感性，后者是通过抑制 GRK2（即 负责心脏 β-AR 脱敏的主要激酶。在目标 2 中，我们将测试是否直接刺激 β3-AR 或 S1PR 提高心肌BDNF含量，保护心肌免遭心肌梗塞；在目标 3 中，我们将 测试长期输注 TrkB 激动剂是否可以挽救因快速起搏引起的心力衰竭的狗的左心室功能 提高心肌效率并恢复β-AR敏感性。拟议的研究意义重大，因为 它有望促进我们对一种新的补偿机制的理解，即 BDNF/TrkB 信号，该信号可以 使心脏在以下条件下保持心肌细胞的功能完整性和能量效率 缺血性或非缺血性应激，并确定 TrkB 激动剂是否值得进一步考虑用于临床 高频测试。