Integrative roles of the sympathetic nervous system and the endothelium in cerebrovascular physiology

概述：我的研究项目旨在更好地了解与器官功能相关的血流控制。这项工作的目标是更好地了解与交感神经系统（通常称为战斗或逃跑反应）和内皮（排列在大脑血管内部的组织）有关的脑血管生理学。具体来说，探索交感神经系统如何影响脑血流的控制，以及交感神经控制的水平是否受到内皮的影响。交感神经系统的作用以及与内皮细胞的相互作用如何影响脑血管功能尚不清楚。这项工作的中心假设是交感神经和内皮细胞的输入施加竞争的影响。也就是说，交感神经使血管变小（血管收缩）的作用被内皮细胞释放的使血管变宽（血管舒张）的物质所掩盖。此外，这些交感神经内皮相互作用在所有脑血管中并不均匀。针对这一假设的具体目标如下：目标：1)在分子水平上确定整个大脑血管中交感神经和初级扩张物质的不同类型和数量；2)使用血管功能测试表征有和没有内皮扩张物质存在时交感神经受体激活的作用。3)确定活体条件下交感神经和内皮功能是否相互作用，共同调节脑血流量。科学方法：这项工作利用猪模型，结合分子、单血管和脑血流血管成像技术，提高我们对哺乳动物脑血管生理学的理解。目的1和2将重点关注脑血管的生化特征和使用分离血管制备的单个血管的匹配功能测试。这些分析将在大脑不同区域的血管中进行。这是在受控条件下研究脑血管生理的理想方法。目的3将重点关注动态条件下活体动物脑血流的调节。这将有助于解释和理解目标1和目标2中发现的生理意义。影响：正在研究的基本过程受到性别、年龄、环境压力、损伤和病理的影响，它们影响大脑功能和行为。因此，这项工作的发现将广泛影响生物科学、人类和兽医科学以及农业工业。本研究将为今后研究脑血流量、脑代谢和认知之间的关系奠定基础，并为对综合生理学感兴趣的年轻科学家和学生提供良好的培训机会。

OVERVIEW: My research program aims to better understand the control of blood flow as it relates to organ function. The goal of this work is to better understand brain blood vessel physiology with respect to the sympathetic nervous system (often called the fight-or-flight response) and the endothelium (a tissue that lines the inside blood vessels in the brain). Specifically, exploring how the sympathetic nervous system influences the control of blood flow in the brain and whether the level of sympathetic control is influenced by the endothelium. The role of the sympathetic nervous system and how interactions with the endothelium influence brain blood vessel function is not clear. The central hypothesis of this work is that sympathetic and endothelial inputs exert competing influences. That is, the effect of the sympathetic nerves to cause blood vessels to get smaller (vasoconstrict) is masked by the release of substances by the endothelium that cause blood vessels to get wider (vasodilate). Further, these sympathetic-endothelial interactions are not uniform across all brain blood vessels. The specific objectives to address this hypothesis are as follows: OBJECTIVES: 1)Identify the different types and number of sympathetic nerves and primary dilator substances in brain blood vessels throughout the brain at the molecular level 2)Characterize the actions of sympathetic nerve receptor activation with and without the endothelial dilator substances present using a blood vessel function test. 3)Determine whether sympathetic nerve and endothelial functions interact and jointly regulate brain blood flow under living conditions. SCIENTIFIC APPROACH: This work utilizes a pig model and combines molecular, single blood vessel and brain blood flow vascular imaging techniques to advance our understanding of mammalian brain blood vessel physiology. Objectives 1 and 2 will focus on biochemical characterization of brain blood vessels and matching functional tests of single blood vessels using an isolated vessel preparation. These analyses will be performed in blood vessels from different brain regions. This is an ideal approach to study brain blood vessel physiology under controlled conditions. Objective 3 will focus on the regulation of blood flow in the brain in live animals under dynamic conditions. This will help interpret and understand the physiological significance of findings from the Objectives 1 and 2. IMPACT: The fundamental  processes being studied are influenced by sex, age, environmental stress, injury and pathology and they affect brain function and behaviour. Thus, findings from this work will broadly influence biological sciences, human and veterinary sciences and agricultural industries. This research will lay the foundation for future work examining the relationship between brain blood flow, brain metabolism and cognition and provides excellent training opportunities for young scientists and students interested in integrative physiology.