Cellular and Molecular Physiology of Sympathetic Innervation of Vascular Smooth Muscle

我的实验室将调节血管平滑肌（VSM）张力，控制血管直径，从而控制血压和血液供应。VSM音调是来自血管神经的收缩和放松信号的平衡。我们关注的是影响我们日常生活的交感神经的收缩信号。过度活跃的交感神经与肥胖和高血压有关，而不活跃的交感神经则会让我们在站立时看到星星。本提案旨在系统、果断地确定VSM的交感调节的三个基本方面。交感神经通过向血管壁的VSM释放几种不同的神经递质来收缩血管。关于这些发射器是一起储存和释放还是单独储存和释放的重要问题仍然没有答案。我们将采用研究中枢神经系统神经元的方法作为解决交感神经细胞SMC控制长期存在的问题的新方法。神经末梢的神经递质释放是由钙通过特殊的电压门控钙通道（n型、P/ q型和r型通道）进入介导的。了解哪个通道介导一个或多个递质的释放对于理解交感神经VSM控制的基础至关重要。尽管有证据表明n型通道的作用，但P/ q型和r型通道在脉管系统中的作用尚不清楚。我们将利用在中枢神经元中研究这些通道的经验来系统地确定这三个通道在不同血管床中的作用。最后，我们将研究线粒体如何整合钙、钠离子、自由基氧和能量代谢信号来调节交感神经递质释放。这些调节途径已经在细胞体和大脑中进行了研究，但线粒体对它们的调节及其相对重要性在调节VSM音调的交感神经中尚不清楚。本研究将为今后研究VSM在疾病和衰老过程中的控制变化奠定基础。

My lab will the regulation of vascular smooth muscle (VSM) tone that controls blood vessel diameter and therefore blood pressure and blood supply. VSM tone is a balance of contractile and relaxing signals from nerves in the blood vessels. We focus on the contractile signals from sympathetic nerves that affect our daily lives. Over-active sympathetic nerves are associated with obesity and hypertension, while under-active sympathetic nerves can cause us to see stars when we stand-up. This proposal aims to systematically and decisively determine three basic aspects of sympathetic regulation of VSM. Sympathetic nerves contract blood vessels by releasing several different neurotransmitters onto the VSM in the blood vessel wall. Important questions remain unanswered about whether these transmitters are stored and released together or independently. We will adapt methods used to study central nervous system neurons as novel approaches to address long-standing questions in sympathetic SMC control. Neurotransmitter release from nerve terminals is mediated by calcium entry through specialized voltage-gated calcium channels called N-type, P/Q-type and R-type channels. Knowing which channel(s) mediates the release of one or more transmitter is essential to understand the basis of sympathetic VSM control. Despite evidence for a role of N-type channels, the roles of P/Q-type and R-type channels in the vasculature is unclear. We will use experience gained studying these channels in central neurons to determine systematically the role of these three channels in differential vascular beds. Lastly, we will study how mitochondria integrate signalling by calcium and sodium ions, radical oxygen species and energy metabolism to regulate sympathetic transmitter release. These regulatory pathways have been studied in cell bodies and in the brain, but their regulation by mitochondria and their relative importance is not known for the sympathetic nerve that regulate VSM tone. This research will form a foundation for future studies of the changes in VSM control in disease and aging.