Modulation of calcium induced calcium release in adren

这一建议是整个PPG主题的组成部分，该主题研究胎儿和成人对高海拔长期缺氧(LTH)的适应。不仅在成人中，在LTH期间暴露于收缩期高血压的胎儿也需要针对大脑侮辱的保护。来自颈上神经节(SCG)的肾上腺素能神经元是应激状态下脑血管收缩和血流调节的重要组成部分。此外，这些神经元在应激条件下调节脑血流，如低氧血症和高血压，降低中风的风险，并减轻蛛网膜下腔出血后的病理严重程度。我们早期发表的数据表明，中脑肾上腺素能神经功能 动脉(MCA)是通过含有神经元型一氧化氮合酶(NNOS)的神经共同支配脑血管而促进的。这些数据表明，在这两种神经类型之间存在着一条复杂的通信路径。我们现在将重点放在SCG上，因为它是一个成熟而有效的模型，用于研究控制肾上腺素能神经细胞内钙离子([Ca2]i)和nNOS神经调节的复杂过程。肾上腺素能神经的功能部分依赖于钙诱导的钙释放(CICR)。 滑面内质网(SER)。CICR放大通过钙通道内流引起的[Ca~(2+)]i升高，并要求SER由通过商店操作的Ca~(2+)通道(SOCC)和SER钙-ATP酶(SERCA)的钙内流来填充。在SCG内，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。结果表明，高原LTH过程中，便捷性nNOS神经功能下降，部分与nNOS蛋白水平下降有关。这些观察结果可能对高原习服过程中的血流分布有一定的指导意义。学习 肾上腺素能神经的调节机制对人类的健康和发育--从胎儿到成人--至关重要。本项目的目标是确定LTH和发育对由SCG产生的肾上腺素能神经元内钙信号的影响以及nNOS神经对这些过程的调节的潜在机制。主导假说是：通过nNOS神经对肾上腺素能神经进行正向调制。 随着LTH的作用，SER钙库的CICR过程或再充盈减少，我们将利用仪器、药理学和分子生物学的一系列技术来探讨LTH应激改变SER钙库再充盈的机制和/或调节绵羊SCG细胞CICR的信号通路。四组受试者分别为：常氧高原习服的成年非孕胎儿和常氧高原习服的近月儿。

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.