Modulation of calcium induced calcium release in adren

钙诱导的肾上腺钙释放的调节

• 批准号: 6875424
• 负责人: J L BUCHHOLZ
• 金额: $ 16.2万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875424
• 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.

该建议是整体PPG主题的组成部分，以研究胎儿和成人对高海拔长期缺氧（LTH）的适应。不仅在成人，而且在LTH期间暴露于收缩期高血压的胎儿中，都需要保护大脑免受脑损伤。肾上腺素能神经元起源于上级颈神经节（SCG），是在这种应激下调节脑血管收缩和血流量的重要组成部分。此外，这些神经元在诸如低氧血症和高血压的应激条件下调节脑血流，降低中风的风险，并减轻蛛网膜下腔出血后病理的严重程度。我们早期发表的数据表明，大脑中动脉肾上腺素能神经功能 通过含有共同支配脑血管系统的神经的神经元型一氧化氮合酶（nNOS）来促进大脑中动脉（MCA）的形成。这些数据表明，这两种神经类型之间存在复杂的通信途径。我们现在专注于SCG，因为它是一个成熟且有效的模型，用于研究控制肾上腺素能神经细胞内钙（[Ca 2 +]i）和nNOS神经调节的复杂过程。肾上腺素能神经的功能部分取决于从肾上腺素能神经释放的钙诱导的钙释放（CICR）。 滑面内质网（SER）。CICR放大了由钙通道内流引起的[Ca 2 +]i增加，并需要通过钙库操纵的钙通道（SOCC）和SERCa 2+-ATP酶（SERCAs）的Ca 2+内流来填充SER。nNOS神经对肾上腺素能神经的易化作用可能部分是由于CICR过程的放大。我们已经表明，在高海拔地区的LTH，这是部分相关的nNOS蛋白水平的下降，facilitatory nNOS神经的功能下降。这些观察结果可能对高海拔LTH习服过程中的血流分布有影响。研究 肾上腺素能神经调节的机制对人类健康和发育（从胎儿到成人）至关重要。该项目的目标是确定LTH和发育对SCG引起的肾上腺素能神经元细胞内钙（[Ca 2 +]）信号传导的影响以及nNOS神经对这些过程的调节的潜在机制。支配性假设是：肾上腺素能神经的正性调节通过nNOS神经通过 LTH可使CICR过程或SER Ca 2+库的再填充功能下降。本研究将采用仪器、药理学和分子生物学等多种技术手段，探讨LTH应激改变分离的绵羊SCG细胞SER Ca 2+库再填充功能和/或调节CICR的信号通路的机制。研究的四个组是：成年非妊娠常氧和高海拔习服组，和近足月胎儿常氧和高海拔习服组。