Regulation of activity-dependent cerebral blood flow by astrocytes

星形胶质细胞对活动依赖性脑血流的调节

• 批准号: RGPIN-2020-05667
• 负责人: Anderson, Christopher
• 金额: $ 2.91万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762099
• 关键词: Regulation; activity; dependent; cerebral; blood

The brain has a high energy demand but virtually no reserve energy capacity. Therefore, it is highly dependent on constant blood and nutrient flow matched dynamically with local energy demand. This is accomplished by a process called functional hyperemia (FH). FH results from creation of molecular signals from active neurons that translate to increases in the lumen diameter of local blood supply vessels and increased blood flow. However, the molecular cell to cell signaling processes that regulate FH and its spatial coordination are poorly understood. My long-term vision is to gain a comprehensive understanding of the intercellular molecular signaling mechanisms responsible for translating neuronal energy need to coordinated local and distal changes in brain vascular lumen diameter and blood flow. We and others have contributed to a wealth of evidence that brain cells called astrocytes are capable of "listening" to synaptic neuronal activity and reacting by sending vasodilatory signals to the local vasculature to increase blood flow. The role of astrocytes in genesis and spatial conduction of FH will be an overarching focus of our short term program objectives. Short term objectives (~5 years) are to: 1.Characterize astrocyte/endothelial signaling mediated by endothelial NMDA receptors 2.Define the role of astrocytes in metabolic control of vasomotor polarity 3.Characterize the role of regional astrocytic heterogeneity in neurovascular coupling 4.Develop models to study astrocyte-endothelial coupling in human neurovascular unit (NVU) Methodologies will address all objectives in a way that ensures high-impact dissemination and attracts and develops exceptional trainees. Models include brain endothelial cell and astrocyte cultures, combined pressure myography with two-photon laser scanning microscopy (TPLSM) of penetrating arterioles in brain slices, TPLSM in awake animals, and modeling of human neurovascular coupling. These approaches will leverage innovative and physiologically integrative technologies and novel leads already produced by my group. We will produce a systematic mechanistic investigation of how astrocytes influence endothelial signaling, vasodilatory neurovascular coupling and functional hyperemia - both in focal locations of enhanced activity and in distal sites due to conducted vasodilation. FH mechanisms describe how neurons are fed according to need as a basic tenet of brain function. Our findings will thus be of broad biological and medical interest to a wide scientific audience. Our program will also illuminate neurovascular coupling mechanisms central to interpretation of functional MRI data in healthy and diseased brain. Finally, our established track record of training HQP with high-impact papers, competitive funding, awards and leading edge of methodological capabilities means our program carries tremendous potential for attraction and training of high quality personnel.

大脑有很高的能量需求，但实际上没有储备能量。因此，它高度依赖于与局部能量需求动态匹配的恒定血液和营养流。这是通过一个称为功能性充血（FH）的过程来实现的。FH是由来自活跃神经元的分子信号的产生引起的，所述分子信号转化为局部供血血管的管腔直径的增加和血流量的增加。然而，调节FH及其空间协调的分子细胞到细胞信号传导过程知之甚少。我的长期愿景是全面了解负责将神经元能量需求转化为脑血管腔直径和血流的协调局部和远端变化的细胞间分子信号传导机制。我们和其他人已经提供了大量证据，证明称为星形胶质细胞的脑细胞能够“倾听”突触神经元的活动，并通过向局部血管系统发送血管舒张信号来增加血流。星形胶质细胞在FH的发生和空间传导中的作用将是我们短期计划目标的首要重点。短期目标（约5年）：1.表征由内皮NMDA受体介导的星形胶质细胞/内皮信号2.确定星形胶质细胞在血管极性代谢控制中的作用3.表征神经血管偶联中局部星形胶质细胞异质性的作用4.建立模型以研究人类神经血管单位（NVU）中星形胶质细胞-内皮偶联。影响传播，吸引和培养优秀的学员。模型包括脑内皮细胞和星形胶质细胞培养物，结合压力肌电图与脑切片中穿透小动脉的双光子激光扫描显微镜（TPLSM），清醒动物中的TPLSM，以及人类神经血管耦合的建模。这些方法将利用创新和生理整合技术和我的团队已经产生的新线索。我们将对星形胶质细胞如何影响内皮信号传导、血管舒张神经血管偶联和功能性充血进行系统的机制研究--无论是在增强活性的焦点位置还是在由于传导性血管舒张的远端部位。FH机制描述了神经元如何根据需要被喂养，作为大脑功能的基本原则。因此，我们的发现将对广大科学受众产生广泛的生物学和医学兴趣。我们的计划还将阐明神经血管耦合机制的核心功能磁共振成像数据在健康和患病的大脑解释。最后，我们在培训HQP方面建立了良好的记录，具有高影响力的论文，有竞争力的资金，奖项和领先的方法能力，这意味着我们的计划具有吸引和培训高素质人才的巨大潜力。