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: 10321551
• 负责人: Scott Earley
• 金额: $ 86.21万
• 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/10321551
• 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; biomedical imaging; 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 脑内血液的最佳流动通过两个过程来确保：（1）自动调节，一种内在的调节机制， 持续调节微循环的机制，以保持恒定的血流， 灌注压的变化，以及（2）神经血管耦合，脑血管系统的整体 这些生理过程使局部血流与组织的代谢活性区域的需要紧密匹配。 个脑袋这些独特的反应是大脑健康和功能所必需的，但仍然不完全 明白此外，微血管控制的丧失与常见的年龄相关性脑血管疾病有关。 病理学，包括卒中、脑小血管疾病（cSVD）和血管性认知障碍，以及 痴呆（VCID）。本提案的总体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，环境，内分泌，旁分泌， 代谢和神经化学刺激在细胞水平上被脑微血管系统感知，以及如何被微血管系统感知。 这些信号被处理以确保体内平衡和适应性。我们的主要机械焦点 研究是瞬时受体电位（TRP）家族的离子通道-多种类型的多模态传感器， 物理和化学刺激存在于所有细胞中。在过去的10年里，我们的研究团队发现， 脑血管平滑肌细胞中的TRPM 4（TRP melastatin 4）和TRPML 1（TRP mucolipin 1）通道 对于肌源性张力的发展是重要的，肌源性张力是一种基本的自动调节机制， 证明了TRPA 1（TRP锚蛋白1）和TRPV 3（TRP香草酸3）通道在神经元上的关键感觉作用。 脑动脉和小动脉的内皮。继续这一主题，并利用先进的生物医学 成像方法和下一代遗传小鼠模型，我们将编织在一起的中心概念 由我们的独立项目建立，以全面概述TRP通道作为蜂窝 大脑微血管中的传感器。拟议研究的例子包括调查， TRP通道信号网络在健康和疾病中的纳米级结构 显微镜下，阐明TRPML 1通道如何在平滑肌细胞中进行内源性调节，以防止 肌源性血管收缩过程中的血管过度收缩，并测试TRPA 1通道对 脑毛细血管内皮细胞作为活性氧物质的检测器以促进神经血管偶联。 我们将对旨在阐明基本调控机制的基础科学研究进行分层， 研究旨在了解TRP通道控制的过程如何出错，并有助于 大脑中健康的小血管在衰老过程中转变为疾病状态。为了实现这一目标，我们 开发和表征与年龄相关的cSVD和VCID的新遗传模型 研究人员在加州大学旧金山分校，并建议利用这一独特的资源，探索主题，包括参与 TRPM 4、TRPML 1和TRPA 1通道在年龄相关cSVD和VCID期间脑血管功能障碍中的作用