Mechanisms of Cardiac TRPV1 Afferent Remodeling in Ventricular Arrhythmias
室性心律失常中心脏 TRPV1 传入重塑的机制
基本信息
- 批准号:10674847
- 负责人:
- 金额:$ 56.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAgonistAnimalsAnti-Arrhythmia AgentsAttenuatedAxonBiological AvailabilityCalcium ChannelCardiacCause of DeathChronicCicatrixClinicalClinical ManagementDataDetectionDevelopmentDrug usageElectrophysiology (science)EpicardiumFamily suidaeFeedbackFiberFunctional disorderGoalsHeartInflammationInterventionIschemiaLinkMapsModelingMyocardialMyocardial InfarctionMyocardial dysfunctionMyocardiumNatureNerveNerve FibersNeuronsNorepinephrineOralPathologicPatient CarePatientsPatternPharmaceutical PreparationsPhasePilot ProjectsPlayResearch PersonnelResiniferatoxinRiskRoleShapesSignal TransductionSiteSpinalSpinal CordStructureStructure of stellate ganglionSympathetic Nervous SystemTRPV1 geneTestingTimeTranslatingVentricular ArrhythmiaVentricular TachycardiaVertebral columnafferent nervebeta-adrenergic receptorclinical translationcomparative efficacyexcitotoxicityfirst-in-humanglial activationin vivoinjuredlocal drug deliverymultidisciplinaryneuralneurochemistryneuroinflammationneuropeptide Yneuroregulationneurotransmissionneurotransmitter releasenovelnovel therapeuticspreventrelease factorside effectsudden cardiac deathtool
项目摘要
PROJECT SUMMARY/ABSTRACT
Myocardial infarction (MI) predisposes patients to ventricular tachycardia/fibrillation (VT/VF) and sudden
cardiac death. After MI, alterations within the cardiac sympathetic nervous system (SNS) have been tightly
linked to VT/VF. These alterations include inflammation, structural and functional remodeling within the stellate
ganglion, and heterogeneous remodeling of intramyocardial sympathetic nerves in the scar-border zone.
These result in enhanced and dysfunctional cardiac sympathetic neurotransmission that lead to VT/VF.
Although spinal afferent signaling is enhanced after MI, the arrhythmogenic potential of spinal afferents (via
maladaptive interactions with cardiac sympathetic nerves) has not been explored. Based on novel data from
our group, the goal of this proposal is to test the hypothesis that chronic enhanced cardiac afferent signaling is
the primary driver of sympathetic neural remodeling and dysfunction that causes VT/VF.
Pilot studies from our group using epicardial resiniferatoxin (RTX) to deplete cardiac TRPV1 afferents in
porcine support the rationale that persistent afferent signaling (beyond the acute ischemic phase) plays a
central role in shaping the neural and cardiac substrates that lead to VAs. We will test our hypotheses using
novel tools from a multidisciplinary team of investigators in 3 aims, in porcine with MI. In aim 1, we will
determine whether post-MI structural, neuroinflammatory, and functional neuronal remodeling within stellate
ganglia are caused by persistent TRPV1 afferent signaling. In aim 2, we will determine whether persistent
cardiac TRPV1 activation amplifies intramyocardial neurotransmitter release to increase VT/VF risk. This will
be accomplished using simultaneous cardiac electrophysiologic mapping and real time in vivo detection of
intramyocardial Norepinephrine and neuropeptide Y levels. We will determine whether TRPV1 afferent
depletion attenuates arrhythmogenicity by normalizing neurotransmitter release patterns. In aim 3, we will
define the optimal site of RTX delivery for clinical management of VT/VF [Epicardial vs. Stellate Ganglion vs.
Epidural application]. This will guide clinical translation of afferent neuromodulation. The results of this proposal
may shift how arrhythmogenesis is approached after MI, and guide the development of new therapies that
prevent altered afferent signaling after MI to fill a major clinical gap.
项目总结/摘要
心肌梗死(MI)易使患者发生室性心动过速/室颤(VT/VF)和突发性室性心动过速/室颤。
心源性死亡心肌梗死后,心脏交感神经系统(SNS)内的变化已被密切关注。
与VT/VF有关。这些改变包括炎症,结构和功能重塑内的星状
神经节和瘢痕边缘区心肌内交感神经的异质性重塑。
这些导致心脏交感神经传递增强和功能障碍,导致VT/VF。
虽然脊髓传入信号在MI后增强,但脊髓传入神经(通过
与心脏交感神经的适应不良的相互作用)尚未被探索。基于来自
我们的小组,这个建议的目标是测试假设,慢性增强心脏传入信号是
交感神经重塑和功能障碍的主要驱动因素,导致VT/VF。
我们小组的初步研究使用心外膜树脂毒素(RTX)消耗心脏TRPV 1传入,
猪支持持续的传入信号(超过急性缺血期)发挥作用的基本原理,
在形成导致VA的神经和心脏基质中起核心作用。我们将使用以下方法来检验我们的假设:
来自多学科研究小组的新工具,用于3个目标,在猪MI中。在目标1中,
确定心肌梗死后星状核内的结构、神经炎症和功能性神经元重塑是否与心肌梗死相关。
神经节是由持续的TRPV 1传入信号引起的。在目标2中,我们将确定是否持久
心脏TRPV 1激活放大心肌内神经递质释放以增加VT/VF风险。这将
使用同时的心脏电生理标测和真实的实时体内检测来完成
心肌内去甲肾上腺素和神经肽Y水平。我们将确定TRPV 1传入
耗尽通过使神经递质释放模式正常化来减弱致心律失常性。在目标3中,我们
定义用于VT/VF临床管理的RTX输送的最佳部位[心外膜vs.星状神经节vs.
硬膜外应用]。这将指导传入神经调节的临床翻译。这一提议的结果
可能会改变MI后的血管生成方式,并指导新疗法的开发,
防止MI后传入信号的改变,以填补主要的临床空白。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Metrics of high cofluctuation and entropy to describe control of cardiac function in the stellate ganglion.
- DOI:10.7554/elife.78520
- 发表时间:2022-11-25
- 期刊:
- 影响因子:7.7
- 作者:Gurel, Nil Z.;Sudarshan, Koustubh B.;Hadaya, Joseph;Karavos, Alex;Temma, Taro;Hori, Yuichi;Armour, J. Andrew;Kember, Guy;Ajijola, Olujimi A.;Zaidi, Mone
- 通讯作者:Zaidi, Mone
Afferents Nerves in Atrial Fibrillation: Going Beyond Fight or Flight.
心房颤动中的传入神经:超越战斗或逃跑。
- DOI:10.1016/j.jacep.2022.01.013
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Hanna,Peter;Ajijola,OlujimiA
- 通讯作者:Ajijola,OlujimiA
Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction.
迷走神经刺激可减少心室心律不齐,并减轻心肌后梗死后神经心脏重塑。
- DOI:10.1016/j.jacbts.2023.03.025
- 发表时间:2023-09
- 期刊:
- 影响因子:9.7
- 作者:Hadaya, Joseph;Dajani, Al-Hassan;Cha, Steven;Hanna, Peter;Challita, Ronald;Hoover, Donald B.;Ajijola, Olujimi A.;Shivkumar, Kalyanam;Ardell, Jeffrey L.
- 通讯作者:Ardell, Jeffrey L.
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Olujimi A Ajijola其他文献
Olujimi A Ajijola的其他文献
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{{ truncateString('Olujimi A Ajijola', 18)}}的其他基金
Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons
交感神经元慢性迷走神经刺激的抗心律失常机制
- 批准号:
10635151 - 财政年份:2023
- 资助金额:
$ 56.61万 - 项目类别:
Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons
交感神经元慢性迷走神经刺激的抗心律失常机制
- 批准号:
10627579 - 财政年份:2023
- 资助金额:
$ 56.61万 - 项目类别:
Core A: Ultrastructural Assessment & Human Tissue
核心 A:超微结构评估
- 批准号:
10627575 - 财政年份:2023
- 资助金额:
$ 56.61万 - 项目类别:
Satellite Glial Cell Activation and Sympathetic Imbalance in Cardiomyopathy and Arrhythmias
心肌病和心律失常中的卫星胶质细胞激活和交感神经失衡
- 批准号:
10416426 - 财政年份:2022
- 资助金额:
$ 56.61万 - 项目类别:
Satellite Glial Cell Activation and Sympathetic Imbalance in Cardiomyopathy and Arrhythmias
心肌病和心律失常中的卫星胶质细胞激活和交感神经失衡
- 批准号:
10599342 - 财政年份:2022
- 资助金额:
$ 56.61万 - 项目类别:
Mechanisms of Cardiac TRPV1 Afferent Remodeling in Ventricular Arrhythmias
室性心律失常中心脏 TRPV1 传入重塑的机制
- 批准号:
10278404 - 财政年份:2021
- 资助金额:
$ 56.61万 - 项目类别:
The University of California - Los Angeles (UCLA) Resident Scientist Training Program (RSTP)
加州大学洛杉矶分校 (UCLA) 驻地科学家培训计划 (RSTP)
- 批准号:
10593059 - 财政年份:2020
- 资助金额:
$ 56.61万 - 项目类别:
The University of California - Los Angeles (UCLA) Resident Scientist Training Program (RSTP)
加州大学洛杉矶分校 (UCLA) 驻地科学家培训计划 (RSTP)
- 批准号:
10373019 - 财政年份:2020
- 资助金额:
$ 56.61万 - 项目类别:
Antiarrhythmic Mechanisms of Bilateral Cardiac Sympathetic Decentralization
双侧心脏交感神经分散的抗心律失常机制
- 批准号:
9182901 - 财政年份:2014
- 资助金额:
$ 56.61万 - 项目类别:
Antiarrhythmic Mechanisms of Bilateral Cardiac Sympathetic Decentralization
双侧心脏交感神经分散的抗心律失常机制
- 批准号:
8804849 - 财政年份:2014
- 资助金额:
$ 56.61万 - 项目类别:
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