TRP channels as fundamental sensors of the cerebral microcirculation

项目总结 大脑中血液的最佳流动由两个过程确保：(1)自动调节，一种内在的 持续调节微循环以保持血液在面对 灌流压的变化，以及(2)神经血管偶联，脑血管的集合 使局部血流量与脑内代谢活跃区域的需求紧密匹配的生理过程 大脑。这些独特的反应对大脑的健康和功能是必要的，但仍不完全 明白了。此外，微血管控制的丧失与常见的年龄相关脑血管有关。 病理，包括中风，脑小血管疾病(CSVD)，血管认知障碍和 痴呆症(VCID)。这项提议的首要目标是通过提供一个 更好地理解大脑不断变化的物理、环境、内分泌、旁分泌、 代谢和神经化学刺激是由脑微血管系统在细胞水平上感知的，以及如何 这些信号经过处理以确保动态平衡和适应性。我们的主要机制重点是 研究的是瞬时受体电位(Trp)家族的离子通道-多种类型的多峰传感器 所有细胞中都存在物理和化学刺激。在过去的10年里，我们的研究团队发现 脑血管平滑肌细胞TRPM4(Trp Melastatin 4)和TRPML1(Trp Mucolipin 1)通道 对肌源性张力的发展很重要，肌张力是一种基本的自我调节机制，并具有 TRPA1(Trp Ankyrin 1)和TRPV3(Trp Vanilloid 3)通道在 脑动脉和小动脉的内皮细胞。继续这个主题，并使用先进的生物医学 成像方法和下一代遗传小鼠模型，我们将把中心概念编织在一起 由我们的独立项目建立，以开发作为蜂窝的TRP渠道的全面概述 大脑微血管系统中的传感器。拟议研究的例子包括将确定 利用超分辨技术研究健康和疾病中Trp通道信号网络的纳米尺度结构 显微镜下，阐明TRPML1通道是如何在平滑肌细胞中内源性调节以防止 在肌源性血管收缩过程中的血管过度收缩，并检验TRPA1通道在 脑毛细血管内皮细胞作为活性氧的检测器，促进神经血管偶联。 我们将对旨在阐明基本调控机制的基础科学调查进行分层 研究旨在了解TRP通道控制的流程如何出错并导致 在衰老过程中大脑中健康的小血管转变为疾病状态。为了推进这一目标，我们正在 与合作开发和表征与年龄相关的csvd和vcid的新遗传模型 加州大学旧金山分校的调查人员，并提议利用这一独特的资源来探索包括参与的主题 TRPM4、TRPML1和TRPA1通道在年龄相关性cSVDS和VCID期间脑血管功能障碍中的作用。

PROJECT SUMMARY Optimal flow of blood within the brain is ensured by two processes: (1) autoregulation, a collection of intrinsic mechanisms that continuously adjust the microcirculation to maintain a constant flow of blood in the face of changes in perfusion pressure, and (2) neurovascular coupling, an ensemble of cerebral vasculature physiological processes that tightly match local blood flow to the needs of metabolically active regions of the brain. These distinctive responses are necessary for brain health and function but remain incompletely understood. Further, loss of microvascular control is associated with common age-related cerebrovascular pathologies, including stroke, cerebral small vessel diseases (cSVDs), and vascular cognitive impairment and dementia (VCID). The overarching goal of this proposal is to address this critical knowledge gap by providing a better understand of how the brain’s ever-changing milieu of physical, environmental, endocrine, paracrine, metabolic, and neurochemical stimuli are sensed by the cerebral microvasculature at the cellular level, and how these signals are processed to ensure homeostasis and adaptability. The primary mechanistic focus of our research is ion channels of the transient receptor potential (TRP) family—polymodal sensors of many types of physical and chemical stimuli present in all cells. Over the past 10 years, our research team has discovered that TRPM4 (TRP melastatin 4) and TRPML1 (TRP mucolipin 1) channels in cerebral vascular smooth muscle cells are important for the development of myogenic tone, a fundamental autoregulatory mechanism, and has demonstrated critical sensory roles for TRPA1 (TRP ankyrin 1) and TRPV3 (TRP vanilloid 3) channels on the endothelium of cerebral arteries and arterioles. Continuing with this theme and using advanced biomedical imaging approaches and next-generation genetic mouse models, we will weave together the central concepts established by our independent projects to develop a comprehensive overview of TRP channels as cellular sensors in the cerebral microvasculature. Examples of proposed studies include investigations that will define the nanoscale architecture of TRP channel signaling networks in health and disease using superresolution microscopy, elucidate how TRPML1 channels are endogenously regulated in smooth muscle cells to prevent vascular hypercontractility during myogenic vasoconstriction, and test the hypothesis that TRPA1 channels on brain capillary endothelial cells act as detectors of reactive oxygen species to promote neurovascular coupling. We will layer basic science investigations intended to elucidate fundamental regulatory mechanisms with research designed to understand how processes controlled by TRP channels go wrong and contribute to the transformation of healthy small vessels in the brain to a disease state during aging. To further this goal, we are developing and characterizing new genetic models of age-related cSVDs and VCID in collaboration with investigators at UCSF, and propose to use this unique resource to explore themes that include the involvement of TRPM4, TRPML1, and TRPA1 channels in cerebral vascular dysfunction during age-related cSVDs and VCID.