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Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

神经营养素和心脏交感神经元的梗死后可塑性

基本信息

批准号：
10439477
负责人：
BETH A HABECKER
金额：
$ 59.36万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439477
关键词：
American Arrhythmia Binding Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiac Output Cause of Death Cells Chemicals Chondroitin Sulfate Proteoglycan Cicatrix Clinical Research Consensus Coronary heart disease Data Denervation Echocardiography Electrocardiogram Electrophysiology (science)Ganglionectomy Genetic Heart Heart Block Heterogeneity Human Imaging Device Immunohistochemistry Infarction Inflammatory Inflammatory Response Intervention Ischemia Isoproterenol Left ventricular structure Life Methods Mus Muscle Cells Myocardial Infarction Nerve Nerve Regeneration Neurons Operative Surgical Procedures Optics Patients Peptides Pharmaceutical Preparations Phosphoric Monoester Hydrolases Predisposition Preparation Process Production Protein Tyrosine Phosphatase Proteomics Reagent Reperfusion Therapy Resistance Risk Role Signal Transduction Sympathectomy Sympathetic Nervous System Telemetry Testing Therapeutic Tissues Ventricular Arrhythmia Work axon growth cardiac repair cell type coronary artery occlusion heart damage heart function high risk in vivo innovation nerve supply neurotransmission neurotrophic factor noradrenergic novel novel therapeutics peptide drug prevent receptor reinnervation sigma receptors small molecule sudden cardiac death tool transmission process

项目摘要

Project Summary Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of sympathetic transmission is a major contributor to post-infarct arrhythmias and sudden cardiac death after myocardial infarction (MI), and sympathetic denervation predicts arrhythmia risk in human studies. During the previous period of support we discovered that persistent denervation was caused by chondroitin sulfate proteoglycans (CSPGs) in the scar acting on neuronal Protein Tyrosine Phosphatase Receptor Sigma (PTPσ). Targeting PTPσ using genetics or the therapeutic peptide ISP promoted reinnervation. Deletion of PTPσ normalized myocyte β-AR signaling, cardiac electrophysiology, and myocyte Ca2+ handling, rendering hearts resistant to isoproterenol-induced arrhythmias. We hypothesize that it is reinnervation, not the lack of PTPσ, which normalizes cardiac electrophysiology and Ca2+ handling after MI. We will test that hypothesis using two therapeutics to restore cardiac nerves: ISP which targets PTPσ, and a novel small molecule (HJ-2) which binds TrkA. This will allow us to distinguish the effects of reinnervation, which is stimulated by both drugs, from other drug-specific effects. We will determine if reinnervation normalizes cardiac electrophysiology and Ca2+ handling, if reinnervation and its effects are sustained, and if noradrenergic transmission is required for restoring electrical stability in the heart. We will determine if sympathetic reinnervation during scar maturation enhances cardiac repair or alters the inflammatory response, and if delayed reinnervation is protective. We have assembled an outstanding team of experts along with novel chemical reagents and imaging tools to assist us in completing these studies. This work will test if stimulating nerve regeneration with therapeutics can normalize cardiac electrophysiology and decrease arrhythmias, and will identify the mechanisms involved.

项目总结

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STAT3 integrates cytokine and neurotrophin signals to promote sympathetic axon regeneration.

DOI：
10.1016/j.mcn.2013.06.005
发表时间：
2013-09
期刊：
MOLECULAR AND CELLULAR NEUROSCIENCE
影响因子：
3.5
作者：
Pellegrino, Michael J.;Habecker, Beth A.
通讯作者：
Habecker, Beth A.

Altered norepinephrine content and ventricular function in p75NTR-/- mice after myocardial infarction.

DOI：
10.1016/j.autneu.2011.05.002
发表时间：
2011-10-28
期刊：
AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL
影响因子：
2.7
作者：
Lorentz, Christina U.;Woodward, William R.;Tharp, Kevin;Habecker, Beth A.
通讯作者：
Habecker, Beth A.

Altered atrial neurotransmitter release in transgenic p75(-/-) and gp130 KO mice.

DOI：
10.1016/j.neulet.2012.08.089
发表时间：
2012-10-31
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Hasan W;Woodward WR;Habecker BA
通讯作者：
Habecker BA

Loss of chondroitin sulfate proteoglycan sulfation allows delayed sympathetic reinnervation after cardiac ischemia-reperfusion.

DOI：
10.14814/phy2.15702
发表时间：
2023-05
期刊：
Physiological reports
影响因子：
2.5
作者：
通讯作者：

Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction.

DOI：
10.7554/elife.78387
发表时间：
2022-05-23
期刊：
ELIFE
影响因子：
7.7
作者：
Blake, Matthew R.;Parrish, Diana C.;Staffenson, Melanie A.;Sueda, Shanice;Woodward, William R.;Habecker, Beth A.
通讯作者：
Habecker, Beth A.