Brain Vascular Heterogeneity

项目概要 在各种神经系统疾病中，已观察到特定的大脑异常。 使用 MRI 和免疫组织学方法对大脑区域进行分析。这些患者包括患有以下疾病的患者 中风、小血管疾病、多发性硬化症和感染性疾病，例如脑卒中 疟疾（CM）。许多神经系统疾病都含有潜在的血管成分。 脑血管病理似乎根据血管大小和特定脑区域的不同而不同 血管驻留，包括驻留在灰质（GM）与白质中的血管的差异 物质（WM）。这些不同的病理在 CM 中尤其明显： WM 但不在 GM 中。人们对这些差异到底是什么以及根本原因知之甚少 GM 与 WM 中的这些血管差异以及这些差异如何与 不同的神经病理学反应。 我们假设，脑微血管源自各种 GM 和 WM 脑 区域，表现出不同的特性，包括转运蛋白、受体的不同表达， 连接分子和细胞粘附分子。这些差异是由于差异 这些大脑的直接生理环境的代谢和功能需求 微血管，包括星形胶质细胞-神经元与周细胞-少突胶质细胞的存在。这些 差异可能是导致不同炎症和出血反应的原因 刺激，例如微生物刺激、中风时缺氧或对 疗法。 在这个提案中，我们打算研究大脑脉管系统的根本差异 使用综合方法使用不同大脑区域的人脑样本 与体外 BBB 建模相结合。我们建议比较 A) 全局表达式 大脑微血管的差异。此后，独特的血管标志物 将选择特定于某些大脑区域并在不同大脑中确认其表达 地区。 B) 将使用体外 BBB 模型测试脑内皮的功能反应 具有反映这些血管差异的特性，例如WM 和 GM 脑内皮。 我们预计该提案将澄清血管差异 不同的大脑区域，并对观察到的不同病理现象提供解释 神经系统疾病。更好地理解血管异质性可能会导致未来 开发新型靶向疗法。

Project Summary In a variety of neurological conditions brain abnormalities have been observed in specific brain areas using MRI and immunohistological methods. These include patients suffering from stroke, small vessel disease, multiple sclerosis and infectious diseases, such as cerebral malaria (CM). Many neurological conditions contain an underlying vascular component. Brain vascular pathologies appear to differ according to vessel size and specific brain area the vessels reside in, including differences in vessels residing in gray matter (GM) versus white matter (WM). These differing pathologies are especially clear in CM: hemorrhagic punctae in WM but not in GM. Little is known of exactly what these differences are, the underlying causes of these vascular differences in GM versus WM and how these differences could relate to divergent neuropathological responses. We hypothesize that, cerebral microvessels derived from various GM and WM brain regions, exhibit differing properties, including different expression of transporters, receptors, junctional molecules and cell adhesion molecules. These differences are due to differences in the metabolic and functional needs of the direct physiological environment of these cerebral microvessel, including presence of astrocyte-neuronal versus pericyte-oligodendrocytes. These differences may be responsible for the varying inflammatory- and hemorrhagic- responses to stimuli, such as microbial stimulation, oxygen deprivation in stroke, or responses to therapeutics. In this proposal we intend to study the underlying differences of the brain’s vasculature using a comprehensive approach using human brain samples of different brain areas in combination with in-vitro BBB modeling. We propose to compare A) the global expression differences of the brain micro-vasculature. Thereafter, distinctive vascular markers that are specific for certain brain areas will be selected and their expression confirmed in different brain areas. B) Functional responses of brain endothelium will be tested using in vitro BBB models that have properties reflecting these vascular differences, e.g. WM and GM brain endothelium. We anticipate that this proposal will lead to clarification of vascular differences in the different brain areas and will offer an explanation for differing pathologies observed in neurological conditions. A better understanding of the vascular heterogeneity may lead to future development of novel targeted therapeutics.