TRP channels as fundamental sensors of the cerebral microcirculation

TRP 通道作为大脑微循环的基本传感器

• 批准号: 10326059
• 负责人: Scott Earley
• 金额: $ 5.26万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326059
• 关键词: ANK1 gene; Address; Aging; Architecture; Basic Science; Blood; Blood Vessels; Blood flow; Brain; Brain region; Capillary Endothelial Cell; Cells; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chemicals; Collaborations; Collection; Development; Disease; Endocrine; Endothelium; Ensure; Family; Genetic; Genetic Models; Goals; Health; Homeostasis; Investigation; Ion Channel; Ischemia; Knowledge; Metabolic; Microcirculation; Microscopy; Perfusion; Physiological Processes; Process; Reactive Oxygen Species; Research; Research Design; Research Personnel; Resources; Role; Sensory; Series; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stroke; TRP channel; TRPA channel; Testing; Vanilloid; age related; arteriole; bioimaging; brain health; cerebral artery; cerebral capillary; cerebral microvasculature; cerebrovascular; cerebrovascular pathology; detector; imaging approach; mouse model; nanoscale; neurochemistry; neurovascular coupling; next generation; paracrine; pressure; prevent; response; sensor; vascular cognitive impairment and dementia; vasoconstriction

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.

项目摘要 通过两个过程确保大脑中血液的最佳流动：（1）自动调节，一系列固有的 连续调整微循环以保持血液流动的机制 灌注压力的变化和（2）神经血管耦合，脑血管的合奏 将局部血流紧密与代谢活性区域的需求紧密相匹配的物理过程 脑。这些独特的反应对于大脑健康和功能是必需的，但仍然不完全 理解齿。此外，微血管控制的丧失与常见的年龄相关脑血管有关 病理学，包括中风，脑小血管疾病（CSVD）和血管认知障碍和 痴呆（VCID）。该提案的总体目标是通过提供一个来解决这一关键知识差距 更好地了解大脑如何改变身体，环境，内分泌，旁分泌的环境， 通过细胞水平的脑微脉管系统感知代谢和神经化学刺激，以及如何 处理这些信号以确保体内稳态和适应能力。我们的主要机械重点 研究是瞬态接收器电势（TRP）家族的离子通道 - 多种类型的验传感器 所有细胞中都存在物理和化学刺激。在过去的10年中，我们的研究团队发现 TRPM4（TRP Melastatin 4）和TRPML1（TRP粘膜1）通道 对于肌源性语调的发展很重要，一种基本的自动调节机制，并且具有 在TRPA1（TRP Ankyrin 1）和TRPV3（TRP Vanilloid 3）通道上展示了关键的感觉角色 脑动脉和动脉的内皮。继续以这个主题并使用高级生物医学 成像方法和下一代遗传小鼠模型，我们将编织中心概念 由我们的独立项目建立，以开发将TRP渠道作为蜂窝的全面概述 脑微脉管系统中的传感器。拟议研究的例子包括将定义的研究 使用超分辨率的健康和疾病中TRP通道信号网络的纳米级体系结构 显微镜检查，阐明如何在平滑肌细胞中内源调节TRPML1通道以防止 肌源性血管收缩期间的血管超收缩性，并测试TRPA1通道的假设 脑毛细管内皮细胞充当活性氧的检测器，以促进神经血管偶联。 我们将对旨在阐明基本法规机制的基础科学调查进行分层 旨在了解TRP渠道控制过程的研究是错误的，并有助于 在衰老过程中，健康的小血管转化为疾病状态。为了进一步，我们是 与年龄有关的CSVD和VCID的新遗传模型开发和表征与VCID的合作 UCSF的调查人员以及使用此独特资源探索包括参与的主题的提议 在与年龄相关的CSVD和VCID期间，脑血管功能障碍中的TRPM4，TRPML1和TRPA1通道