NGF and Post-Infarct Sympathetic Neuroplasticity

NGF 和梗死后交感神经可塑性

• 批准号: 7035264
• 负责人: Peter G Smith
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035264
• 关键词: adrenergic receptor; antiadrenergic agents; enzyme linked immunosorbent assay; heart innervation; histology; immunofluorescence technique; in situ hybridization; inflammation; laboratory rat; molecular /cellular imaging; morphometry; myocardial infarction; nerve growth factors; nervous system regeneration; neural inhibition; neural plasticity; pathologic process; polymerase chain reaction; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Arrhythmias and cardiac dysfunction occur when sympathetic neural influences are excessive. Recent evidence indicates that structural remodeling of cardiac nerves contributes to hyperexcitability. Because nerve growth factor (NGF) is the major protein regulating sympathetic innervation, it is implicated in sympathetic neuroplasticity. In the present application we test the hypothesis that abnormal NGF synthesis after myocardial infarction leads to cardiac sympathetic nerve remodeling. We propose that abnormally high NGF expression in peri-infarct inflammatory myofibroblasts and macrophages contributes to hyperinnervation, and that deficient NGF expression in parasympathetic neurons leads to loss of parasympathetic presynaptic inhibition of sympathetic nerves. The long-term goals of this study are to understand the molecular mechanisms that regulate cardiac sympathetic innervation and to devise interventional strategies to correct abnormal innervation patterns. Experiments in Aim 1 demonstrate that coronary artery ligation in rats upregulates NGF in specific subsets of inflammatory cells. Aim 2 explores temporo-spatial features of ingrowth of identified axons and assesses the role of trophic factors in this process. Aim 3 investigates if sympathetic innervation itself promotes inflammatory cell NGF expression via beta adrenergic receptors. In Aim 4 we assess whether NGF expression in cardiac parasympathetic neurons, which may govern formation of axo-axonal inhibitory synapses, is regulated by sympathetic innervation. In Aim 5 we examine the role of adrenergic receptors in regulating cardiac parasympathetic NGF synthesis. Aim 6 investigates the possibility that adrenergic receptor down-regulation leads to diminished cardiac parasympathetic NGF synthesis in heart failure. Aim 7 investigates whether reduced parasympathetic NGF can account for diminished axo-axonal inhibition in heart failure. We use morphometric histochemistry, cell and tissue culture, protein and mRNA assays, and in vivo recordings to attain these goals. These studies will provide new and important information on molecular mechanisms regulating sympathetic neuroplasticity within the damaged heart, thus providing a more complete understanding of post-infarct cardiac dysfunction. Importantly, they will provide novel data on how trophic factor synthesis is regulated by adrenergic receptors, and may serve as a basis for pharmacological interventions aimed at preventing or reversing deleterious cardiac sympathetic remodeling.

描述（由申请人提供）：当交感神经影响过度时，会发生心律失常和心功能障碍。最近的证据表明，心脏神经的结构重塑有助于过度兴奋。由于神经生长因子（NGF）是调节交感神经支配的主要蛋白质，因此它与交感神经可塑性有关。在本申请中，我们检验了心肌梗死后异常NGF合成导致心脏交感神经重塑的假设。我们建议，异常高的NGF表达梗死周围炎性肌成纤维细胞和巨噬细胞有助于hypernerveduction，并在副交感神经元中缺乏NGF表达导致交感神经的副交感神经突触前抑制的损失。本研究的长期目标是了解调节心脏交感神经支配的分子机制，并设计干预策略来纠正异常的神经支配模式。目的1中的实验证明，大鼠冠状动脉结扎上调炎症细胞特定亚群中的NGF。目的2探索轴突长入的时空特征，并评估营养因子在此过程中的作用。目的3研究交感神经支配本身是否通过β肾上腺素能受体促进炎性细胞表达NGF。在目的4中，我们评估是否在心脏副交感神经元，这可能会导致轴-轴抑制性突触的形成，神经生长因子的表达受到交感神经支配。在目的5中，我们研究了肾上腺素能受体在调节心脏副交感神经NGF合成中的作用。目的6探讨心力衰竭时肾上腺素能受体下调导致心脏副交感神经NGF合成减少的可能性。目的7调查是否减少副交感神经神经生长因子可以解释减少轴索轴突抑制心力衰竭。我们使用形态组织化学，细胞和组织培养，蛋白质和mRNA测定，并在体内记录，以达到这些目标。这些研究将提供新的和重要的信息，在受损的心脏交感神经可塑性的分子机制调节，从而提供了一个更完整的了解梗死后心功能不全。重要的是，它们将提供关于营养因子合成如何受肾上腺素能受体调节的新数据，并可作为旨在预防或逆转有害的心脏交感神经重塑的药理学干预的基础。