NGF and Post-Infarct Sympathetic Neuroplasticity

描述（由申请人提供）：交感神经影响过大时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高兴奋性。由于神经生长因子（NGF）是调节交感神经支配的主要蛋白，它与交感神经的可塑性有关。在本应用中，我们验证了心肌梗死后NGF合成异常导致心脏交感神经重构的假设。我们认为，在梗死周围炎性肌成纤维细胞和巨噬细胞中异常高的NGF表达有助于神经亢进，而副交感神经元中NGF表达不足导致副交感神经突触前抑制的丧失。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，并制定纠正异常神经支配模式的干预策略。Aim 1的实验表明，大鼠冠状动脉结扎可上调特定炎症细胞亚群中的NGF。目的2探讨已识别轴突生长的时空特征，并评估营养因子在这一过程中的作用。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症细胞NGF的表达。在Aim 4中，我们评估了NGF在心脏副交感神经细胞中的表达是否受到交感神经支配的调节。NGF可能控制轴-轴突抑制性突触的形成。在Aim 5中，我们研究了肾上腺素能受体在调节心脏副交感神经生长因子合成中的作用。目的6探讨肾上腺素能受体下调导致心衰时心脏副交感神经生长因子合成减少的可能性。目的7研究副交感神经生长因子的减少是否可以解释心衰中轴突抑制的减少。我们使用形态计量学组织化学、细胞和组织培养、蛋白质和mRNA测定以及体内记录来实现这些目标。这些研究将为损伤心脏内调节交感神经可塑性的分子机制提供新的重要信息，从而为梗死后心功能障碍提供更完整的认识。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，并可能作为旨在预防或逆转有害心脏交感神经重构的药物干预的基础。

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.