Quantitative analysis of estrogen and sleep deprivation-induced blood and lymphatic vascular remodeling in the brain system

摘要 组成中枢神经系统血液和淋巴管网的众多小血管 异质和特定于区域的动态结构，其分段、位置、形状和功能可以 对生理和病理生理条件作出反应的变化。到目前为止，还不可能 整合血液和淋巴血管要素及其微环境，实现整体 脑和脑膜组织尺度联合血管网络的定量表征及其 正常和疾病状态下的结构和功能。这个应用程序建议发展显微镜- 基于高通量图像分析技术的血液和淋巴管自动提取 支持脑血管微环境的定量形态动力学表征的网络 两个脑室--脑和硬脑膜的变化。这项研究将集中在新的 精确的区域特定微血管配准、镶嵌、分割、融合和 共定位构建大组织尺度空间排列的双血/淋巴管网络 两性动物的结构图谱以及微血管异质性的表征 网络，包括血液和淋巴管系统，在雌激素和睡眠剥夺(条件)下 与多种脑血管疾病相关)与生理环境相比。换句话说， 先进的基于显微镜的技术将被用于亚微米级的血管和淋巴管成像 在硬脑膜和大脑中的分辨率，然后进行前沿的深度机器学习成像分析 这些方法将被用来分割和量化这些血管、它们的几何形状、管壁结构 功能性和相互关系。对微血管网络的详细结构分析对于 准确评估废物的物力分布、底物输送和组织清除， 以及生理和心理状态下颅内神经网络重塑的性别差异和后果 病理情况。这将创造知识，使人们能够更好地了解 雌激素和睡眠剥夺下的血管损伤，确定共同的分子机制和 不同治疗方法的疗效和疗效。如果没有能力构建总 来自仅限于单个组织的研究的结构和功能血液/淋巴管网络图 组成部分，难怪从分子和细胞水平到整个器官的翻译 和系统级别是有缺陷的，并阻碍了向全面理解的翻译进展 与一系列神经紊乱有关的病理生理学。

Abstract Numerous small vessels making up the central nervous system blood and lymphatic vascular networks are heterogeneous and region-specific dynamic structures, whose segments, position, shape and function can change in response to physiological and pathophysiological conditions. To date it has not been possible to integrate blood and lymphatic vascular elements and their microenvironment to achieve a holistic quantitative characterization of the combined brain and meningeal tissue-scale vascular networks, its structure and function in normal and disease states. This application proposes to develop microscopy- based high-throughput image analysis techniques for automated extraction of blood and lymphatic vascular networks enabling quantitative morphodynamic characterization of cerebrovascular microenvironment changes in two intracranial compartments – the brain and dura mater. The study will focus on new algorithms for precise region-specific microvessel registration, mosaicing, segmentation, fusion and colocalization for constructing large tissue scale spatially aligned dual blood/lymphatic vascular network structural maps in the animals of both sexes, as well as characterization of heterogeneities of microvascular networks, including blood and lymphatic vasculature, under estrogen and sleep deprivation (the conditions relevant to multiple cerebrovascular disorders) compared to physiological settings. In other words, advanced microscopy-based techniques will be used to image blood and lymphatic vessels at sub-micron resolution in dura mater and the brain, and then cutting-edge deep machine learning imaging analysis methods will be employed to segment and quantify these vessels, their geometry, vessel wall structure, functionality, and interrelationship. Detailed structural analysis of microvascular networks is essential for accurate evaluation of the distribution of physical forces, substrate delivery and tissue clearance of waste, as well as sex differences and consequences of intracranial networks remodeling under physiological and pathological conditions. This will create knowledge enabling a better understanding of the pathogenesis of vascular impairments under estrogen and sleep deprivation, identify common molecular mechanisms and the efficacy and effectiveness of different therapeutic treatments. Without the ability to construct total structural and functional blood/lymphatic vascular network maps from studies limited to individual tissue component parts, it is little wonder that translation from the molecular and cellular levels to the whole organ and system levels is deficient and hinders translational progress towards a comprehensive understanding of the pathophysiology associated with a range of neurological disorders.