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：
10287657
负责人：
Nazareno Paolocci
金额：
$ 35.39万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287657
关键词：
ADRBK1 gene Accounting Agonist Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amendment Amyloid beta-Protein Anxiety Attenuated Behavioral Binding Biochemical Brain Brain Diseases Brain-Derived Neurotrophic Factor Canis familiaris Cardiac Chronic Cognitive Deposition Deterioration Diagnosis Dilated Cardiomyopathy Disease EFRAC Evaluation FDA approved Failure Functional disorder Generations Genes Healthcare Heart Heart Diseases Heart failure Individual Infusion procedures Link Mental Depression Modeling Moods Mus Muscle Cells Myocardial Neurodegenerative Disorders Neurons Orphan Parents Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Performance Peripheral Nervous System Phenotype Phosphotransferases Play Protocols documentation Publishing Role Signal Transduction Testing Therapeutic Tropomyosin United States National Institutes of Health Up-Regulation Work abeta accumulation base behavioral study cognitive ability druggable target effective therapy foot heart function hyperphosphorylated tau improved long term memory mouse model neurotrophic factor neurotropic novel pre-clinical preservation prevent prospective receptor small molecule sphingosine 1-phosphate tau Proteins therapeutically effective

项目摘要

Project Summary Alzheimer’s disease (AD) and heart failure with preserved ejection fraction (HFpHF) are highly prevalent diseases. Recent findings show the alarming prospective that they can intertwine in the same individuals. For both conditions, the therapeutic options remain scant. Following the NIH initiative directed to penetrate the pathogenesis of either of these diseases to unearth more effective therapeutic options, here we propose to investigate a new mechanism that AD and HFpEF may have in common and that can unveil a unifying therapeutic approach for both diseases. That is: that the concomitant cardiac and central loss in brain-derived neurotrophic factor (BDNF) and its associated receptor, tropomyosin receptor kinase B (TrkB) accounts for Aβ pathology and hyperphosphorylated tau deposition and vice-versa, contributing to the onset and progression of AD and HFpHF. In turn, these two conditions negatively reverberate on each other. Here, we propose two aims. In the first Aim, using unique gene-edited mouse lines for cardiac and neuronal BDNF/TrkB signaling, we will determine whether a lack of TrkB/BDNF signaling fuels Aβ and/or tau pathology, triggering HFpEF and, in turn, the accumulation of Aβ and/or tau in the heart underlies HFpEF pathogenesis via reduced expression of TrkB/BDNF signaling. In the second Aim, we will test the impact of specific, agonist-based TrkB stimulation prevents the accumulation of Aβ and hyperphosphorylated tau in the heart and brain of AD, improving both cognitive/locomotor and diastolic dysfunction.Of note, in the present proposal, we will put the evaluation of myocardial performance on equal footing with that of central functions. Indeed, in all mouse protocols performed here, we will conduct behavioral studies apt to evaluate cognitive abilities (such as short- and long-term memory) and mood control (anxiety and depression) to determine whether an improvement of cardiac function via TrkB agonists attenuates behavioral alterations typically found in patients with AD or HFpEF, or vice versa. The functional parameters will be also paralleled by the biochemical and pathological assessment, key for the diagnosis of proteinopathies and for the analysis of the mechanisms.

项目概要阿尔茨海默病 (AD) 和射血分数保留的心力衰竭 (HFpHF) 是高度最近的研究结果表明，它们可能相互交织在一起，这一前景令人担忧。对于这两种情况，美国国立卫生研究院 (NIH) 的治疗选择仍然很少。旨在深入了解这两种疾病的发病机制以发现更多有效的治疗选择，在这里我们建议研究 AD 和 HFpEF 可能有共同点，可以为两者提供统一的治疗方法即：伴随心脏和中枢的脑源性神经营养丧失。因子 (BDNF) 及其相关受体、原肌球蛋白受体激酶 B (TrkB) 负责 Aβ 病理学和过度磷酸化 tau 沉积，反之亦然，有助于发病和 AD 和 HFpHF 的进展反过来，这两种负面状况相互影响。在这里，我们提出了两个目标，第一个目标是使用独特的基因编辑小鼠品系来治疗心脏疾病。和神经元 BDNF/TrkB 信号传导，我们将确定是否缺乏 TrkB/BDNF 信号传导促进 Aβ 和/或 tau 病理，触发 HFpEF，进而导致 Aβ 和/或 tau 积累心脏中 TrkB/BDNF 信号表达减少是 HFpEF 发病机制的基础。第二个目标，我们将测试特定的、基于激动剂的 TrkB 刺激对预防 Aβ 和过度磷酸化的 tau 蛋白在 AD 患者的心脏和大脑中积累，从而改善两者认知/运动和舒张功能障碍。值得注意的是，在本提案中，我们将把事实上，心肌性能的评估与中枢功能的评估处于同等地位。此处执行的小鼠协议，我们将进行易于评估的行为研究能力（例如短期和长期记忆）和情绪控制（焦虑和抑郁）确定通过 TrkB 激动剂改善心脏功能是否会减弱行为通常在 AD 或 HFpEF 患者中发现的改变，反之亦然。同时还将进行生化和病理评估，这是诊断的关键蛋白质病及其机制分析。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Hydropersulfides (RSSH) Outperform Post-Conditioning and Other Reactive Sulfur Species in Limiting Ischemia-Reperfusion Injury in the Isolated Mouse Heart.

氢过硫化物 (RSSH) 在限制离体小鼠心脏缺血再灌注损伤方面优于后处理和其他反应性硫物质。

DOI：
发表时间：
2022-05-20
期刊：
影响因子：
0
作者：
Pharoah, Blaze M;Khodade, Vinayak S;Eremiev, Alexander;Bao, Eric;Liu, Ting;O'Rourke, Brian;Paolocci, Nazareno;Toscano, John P
通讯作者：
Toscano, John P

Aldosterone Jeopardizes Myocardial Insulin and β-Adrenergic Receptor Signaling via G Protein-Coupled Receptor Kinase 2.

醛固酮通过 G 蛋白偶联受体激酶 2 危害心肌胰岛素和 β-肾上腺素能受体信号传导。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Cannavo, Alessandro;Marzano, Federica;Elia, Andrea;Liccardo, Daniela;Bencivenga, Leonardo;Gambino, Giuseppina;Perna, Claudia;Rapacciuolo, Antonio;Cittadini, Antonio;Ferrara, Nicola;Paolocci, Nazareno;Koch, Walter J;Rengo, Giuseppe
通讯作者：
Rengo, Giuseppe

Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1.

心肌脑源性神经营养因子通过转录因子 Yin Yang 1 调节心脏生物能。

DOI：
发表时间：
2023-03-31
期刊：
影响因子：
10.8
作者：
Yang, Xue;Zhang, Manling;Xie, Bingxian;Peng, Zishan;Manning, Janet R;Zimmerman, Raymond;Wang, Qin;Wei, An;Khalifa, Moustafa;Reynolds, Michael;Jin, Jenny;Om, Matthew;Zhu, Guangshuo;Bedja, Djahida;Jiang, Hong;Jurczak, Michael;Shiva, Srut
通讯作者：
Shiva, Srut

Enhanced Myocardial Adenylyl Cyclase Activity Alters Heart-Brain Communication.

增强的心肌腺苷酸环化酶活性改变心脑通讯。

DOI：
发表时间：
2023-11
期刊：
影响因子：
0
作者：
Agrimi, Jacopo;Menicucci, Danilo;Qu, Jia;Laurino, Marco;Mackey, Chelsea D;Hasnain, Laila;Tarasova, Yelena S;Tarasov, Kirill V;McDevitt, Ross A;Hoover, Donald B;Gemignani, Angelo;Paolocci, Nazareno;Lakatta, Edward G
通讯作者：
Lakatta, Edward G

Empagliflozin and HFrEF: Known and Possible Benefits of NHE1 Inhibition.

Empagliflozin 和 HFrEF：NHE1 抑制的已知和可能的益处。