神经肽Y及其受体调节通路—血压神经调控性别差异的新靶点

Neuropeptide Y, a neurotransmitter, that is consist of 36 amino acids and secreted from hypothalamus, plays a wide physiological functions on food in taking, emotional controlling, and cardiovascular regulation. More importantly, NPY has a much greater impacts on multiple life threatening health problems, such as obesity, diabetes, and hypertension. NPY and its receptors are found to express in both neurons located in nodose ganglia (NG) and nucleus of tractus solitary (NTS), which are the first- and second-order neurons in the afferent loop of baroreflex. The evidence has shown that NPY regulates the neuronal excitability through multiple ion channel functions and participates in the regulation of central and peripheral blood pressure. As we all know, the gender difference in the physiological blood pressure and the incidence of hypertension is still a hot topic in the field of research. Intriguingly, it has been confirmed that there is a significant gender difference in NPY and affiliated receptor function, including NPY-mediated cardiovascular events. Based upon our preliminary data and published evidence, our central hypothesis is that the interaction between NPY and metabolic factors, modulation of related signal pathway and regulation female-specific distribution of myelinated Ah-type baroreceptor neurons, which will play an important role in the neurocontrol of circulation/baroreflex function and hypertensive pathological process. To test this hypothesis, NG-nitro-L-Arginine methylester injection (L-NAME), high fructose drinking (HFD) induced hypertension, and the spontaneous hypertension (SHR) rat models will be used to interdisciplinary investigate the potential role of NPY and its receptors in gender difference in neurocontrol of circulation and blood pressure regulation using functional, molecular biological and electrophysiological approaches conjugated with in vivo and in vitro techniques. The result and conclusion from this cross-over and translational medical research regarding to two major systems, neuroscience and circulation with multiple levels investigations of current proposed project will reveal the effects of NPY and its receptors, which will be a perspective target in the field of research.

神经肽Y（NPY）是下丘脑分泌的神经递质,参与进食、情绪及心血管功能调节,与多种病理生理过程（肥胖症，糖尿病，及高血压）密切相关。NPY及受体广泛分布于结状神经节和孤束核，调控离子通道和神经元功能，参与中枢及外周血压的调控。众所周知，生理血压和高血压发病的性别差异仍是当今研究热点。前期结果显示压力反射传入通路中NPY受体表达性别差异明显，结合我们多项研究成果提出了本申请的中心科学假设，即NPY可通过与代谢因子的相互作用，调控相关信号通路，作用于雌性特异分布的髓鞘化Ah-型压力感受器神经元，参与神经系统血压调控的性别差异及高血压的病理过程。故本申请将构建一氧化氮缺失、代谢异常继发和自发性高血压大鼠动物模型，采用功能及分子生物学与膜片钳技术，离体和在体实验及神经和循环两大系统交叉的转化医学理念，阐明NPY参与血压神经调控性别差异的作用机制，使其成为血压神经调控研究的新亮点。

神经肽Y作为代谢相关的心血管因子，在外周和中枢通路对血压的调控发挥重要作用。前期结果显示NPY及受体在结状神经节和孤束核中的表达存在性别差异，其中雌性特异分布的髓鞘化Ah-型压力感受器神经元作为研究重点，结合功能及分子生物学与膜片钳技术，研究了在不同高血压状态下，NPY 及相关代谢因子的表达与功能变化，阐明NPY调控血压的病理过程和电生理学机制。同时本课题还研究了副交感神经在压力反射传入通路细胞水平上发挥的主导作用及其在血压调节中的神经调控机制。此外， 成纤维细胞生长因子-21（FGF-21）、过氧化物酶体增殖物激活受体（PPAR-a）的激动剂非诺贝特和引起血管舒张和血压下降的神经递质P物质均可通过压力反射传入环路参与血压性别差异调节并在代谢紊乱相关的高血压疾病中也起到关键作用。研究发现：1）在压力感受器神经元中，Y1受体可随高血压的病理过程发生改变，但雌激素可能在某种程度上干预了Y2受体在病理状态下的表达；在外周神经系统中，NPY在维持自发性高血压大鼠的血压平衡中与其他神经递质相比，不扮演重要的角色，但其中枢作用体现的更为突出； NPY可通过Y1受体/Y2受体影响雌性特异性分布的髓鞘化Ah-型压力感受器神经元的兴奋性来参与血压神经调控产生性别差异。2）利用膜片钳技术检测成年雌性大鼠的迷走神经和脑干切片，在药理学和电生理学上，仅在有髓鞘的A -和Ah -型压力感受器神经元中可见静息膜电位的自发活动和突触电流。与抑制性突触后电流（IPSCs）相比，仅在Ah-型神经元中可观察到较大的兴奋性突触后电流（EPSCs）的频率和振幅，这可能是使雌性血压维持较低水平的重要原因。3）FGF-21 /FGFRs和SP/ NKR均可通过压力反射传入通路参与血压性别差异调节。4）非诺贝特可部分通过PPAR介导的UCP2表达上调和减少氧化应激改善压力反射传入功能，在血压的神经调控中发挥关键作用。本项目发表与课题相关SCI收录论文5篇。参与多个国内外学术会议，共培养硕士研究生16名，毕业8名。