Modulation of calcium induced calcium release in adren

钙诱导的肾上腺钙释放的调节

• 批准号: 7312347
• 负责人: J L BUCHHOLZ
• 金额: $ 16.61万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312347
• 关键词: age difference; altitude; brain circulation; calcium flux; embryo /fetus; embryo /fetus hypoxia; endoplasmic reticulum; environmental adaptation; hypoxia; nitric oxide synthase; norepinephrine; sheep; superior cervical ganglion; vascular smooth muscle nervous control; vasomotion

This proposal is integral to the overall PPG theme to study fetal and adult adaptations to long-term hypoxia (LTH) at high altitude. Protection is needed against cerebral insults not only in the adult but also in the fetus exposed to systolic hypertension during LTH. Adrenergic neurons, arising from the superior cervical ganglion (SCG), are an important component of the regulation of cerebral blood vessel contractility and blood flow under this stress. Furthermore, these neurons regulate cerebral blood flow under stress conditions such as hypoxemia and hypertension, reducing the risk of stroke, and attenuating severity of pathology following subarachnoid hemmorhage. Our earlier published data show that adrenergic nerve function in middle cerebral arteries (MCA) is facilitated via neuronal nitric oxide synthase (nNOS) containing nerves co-innervating the cerebral vasculature. These data suggest that there is a complex communication pathway between these two nerve types. We now are focusing on the SCG as it is a well established and efficient model for studying the complex processes that control intracellular calcium ([Ca2+]i) in adrenergic nerves and modulation by nNOS nerves. The function of adrenergic nerves depends in part on calcium induced calcium release (CICR) from the smooth endoplasmic reticulum (SER). CICR amplifies increased [Ca2+]i caused by influx through Ca2+ channels and requires that SER be filled by Ca 2+ influx through store operated Ca2+ channels (SOCC) and SER Ca 2+-ATPases (SERCAs). The faciliatory function of nNOS nerves on adrenergic nerves in the SCG may, in part, be due to amplification of the CICR process. We have shown that the function of faciliatory nNOS nerves declines during LTH at high altitude, which is partly related to a decline in nNOS protein levels. These observations may have implications for the distribution of blood flow during LTH acclimatization at high altitude. Studying mechanisms underlying the regulation of adrenergic nerves is vital to human health and development -- from fetus to adult. The project goal is to determine mechanisms underlying the impact of LTH and development on intracellular calcium ([Ca2+]) signaling in adrenergic neurons arising from the SCG and modulation of these processes by nNOS nerves. The governing hypothesis is: positive modulation of adrenergic nerves via nNOS nerves through the CICR process or refilling of SER Ca 2+ stores declines in response to LTH, We will use a range of techniques, instrumental, pharmacological and molecular to probe the mechanisms by which LTH stress may alter the refilling of SER Ca 2+ stores and/or the signaling pathway responsible for modulating CICR in isolated sheep SCG cells. The four groups to be studied are: adult non-pregnant normoxic and high altitude acclimated, and near term fetus, normoxic and high altitude.

该提案是研究高海拔地区长期缺氧（LTH）的胎儿和成人适应的总体PPG主题不可或缺的一部分。不仅需要在成年人中而且在LTH期间暴露于收缩压的胎儿中，还需要保护脑损伤。肾上腺神经节（SCG）引起的肾上腺素能神经元是调节这种压力下脑血管收缩性和血流的重要组成部分。此外，这些神经元在低氧血症和高血压等应激条件下调节脑血流量，降低了中风的风险，并减轻了蛛网膜下腔hem虫后病理的严重程度。我们较早发布的数据表明，肾上腺功能的功能在大脑中部 动脉（MCA）通过神经元氧化物合酶（NNOS）促进，这些神经含有神经，使大脑血管共同发挥作用。这些数据表明，这两种神经类型之间存在复杂的通信途径。我们现在关注SCG，因为它是一个良好而有效的模型，用于研究肾上腺神经中控制细胞内钙（[Ca2+] i）的复杂过程，并通过NNOS神经进行调节。肾上腺素神经的功能部分取决于钙诱导的钙释放（CICR） 光滑的内质网（Ser）。 CICR放大了通过Ca2+通道涌入引起的[Ca2+] I的增加[Ca2+] i，并要求通过CA 2+涌入通过存储操作的Ca2+通道（SOCC）和Ca 2+ -ATPases（SERCAS）填充Ser。 NNO神经在SCG中肾上腺能神经上的促进功能可能部分是由于CICR过程的扩增。我们已经表明，在高海拔地区LTH期间，促进NNOS神经的功能与NNOS蛋白水平下降有关。这些观察结果可能对在高海拔的LTH适应过程中的血流分布有影响。研究 从胎儿到成人，肾上腺能神经调节的机制对于人类健康和发育至关重要。项目目标是确定LTH和发育对细胞内钙（[CA2+]）信号的影响的机制，该肾上腺神经元是由NNOS神经对这些过程引起的肾上腺素能神经元的。管理假设是：通过nnos神经通过非肾上腺神经进行正面调节 CICR工艺或Ser Ca 2+商店的重新填充对LTH的响应下降，我们将使用一系列技术，药理和分子的技术来探测LTH应力可能会改变Ser Ca 2+商店的补充和/或负责调节CICR在分离的Sheep SCG细胞中调节CICR的机制。要研究的四个组是：成年非孕妇常氧和高海拔适应，近期胎儿，常氧和高海拔。