Brain Vascular Heterogeneity

项目摘要 在各种神经疾病中，脑异常在特定情况下被观察到。 使用MRI和免疫组织学方法检测大脑区域。这些患者包括患有 中风、小血管疾病、多发性硬化症和传染病，如脑部疾病 疟疾(CM)。许多神经系统疾病都含有潜在的血管成分。 脑血管病变似乎根据血管大小和特定的脑区而有所不同。 血管驻留在，包括驻留在灰质(GM)和白色的血管的差异 物质(WM)。这些不同的病理在CM中尤其明显：点状出血 WM但不是通用汽车。对于这些差异到底是什么，根本原因是什么，我们知之甚少 GM和WM的这些血管差异以及这些差异如何与 不同的神经病理反应。 我们推测，脑微血管来源于不同的GM和WM脑 区域，表现出不同的特性，包括不同的转运体，受体， 连接分子和细胞黏附分子。这些差异是由于 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反应和出血反应的原因 刺激，如微生物刺激，中风时的缺氧，或对 治疗学。 在这项提议中，我们打算研究大脑血管系统的潜在差异 使用一种综合方法，使用人脑不同区域的样本 结合体外血脑屏障模型。我们建议比较A)全局表达式 脑微血管系统的差异。此后，独特的血管标志物 将选择特定的大脑区域，并确认它们在不同大脑中的表达 区域。B)将使用体外血脑屏障模型测试脑内皮细胞的功能反应 具有反映这些血管差异的特性，例如WM和GM大脑内皮。 我们预计，这项建议将导致澄清血管的差异 不同的大脑区域，将为观察到的不同病理提供解释 神经方面的情况。对血管异质性的更好理解可能会导致未来 开发新的靶向疗法。

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.