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

基本信息

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
项目类别：
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

项目摘要

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删除肌细胞中的 BDNF 会导致基线时出现明显的左心室扩张，但我们的试点数据从未在 cBDNF-/- 小鼠中测试过基础和应激刺激的左心室 (LV) 功能。表明人类和实验性心力衰竭受试者的左心室大量 BDNF 耗尽。根据实验和临床证据，心脏 BDNF/TrkB 的长期目标仍处于很大程度上未被充分研究。确定导致衰竭心脏中 BDNF/TrkB 信号丢失的因素，以及重新定位的机制通过 TrkB 刺激在 BDNF 耗尽的衰竭心脏中引入 BDNF，可以防止缺血和心肌梗塞在此我们提出以下三个新假设：1）心肌BDNF。防止梗塞心脏世代慢性心脏失代偿，适当的 βAR 活性参与其中在这一代中；2) 直接刺激 S1PR 可增强心肌 BDNF 的产生，从而预防 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 刺激可挽救； 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导致的心肌细胞损失相关的临床相关病症我们将在目标 1 中确定三个综合具体目标来检验中心假设。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（可能导致心脏 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，保护心肌免受心肌梗塞的侵害；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敏感性这项研究意义重大，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。