Brain Vascular Heterogeneity

脑血管异质性

• 批准号: 10437595
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 23.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437595
• 关键词: Affect; Area; Astrocytes; Basal Ganglia; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; Brain region; Cell Adhesion Molecules; Cell Communication; Cerebral Malaria; Cerebrovascular system; Cerebrum; Characteristics; Communicable Diseases; Communication; Corpus Callosum; Data; Development; Disease; Endothelium; Environment; Erythrocytes; Exhibits; Future; G-Protein-Coupled Receptors; Gene Chips; Gene Expression; Genes; Genetic Transcription; HIV; Hemorrhage; Heterogeneity; Human; Immune; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Lead; Liver; Magnetic Resonance Imaging; Metabolic; Methods; Microvascular Dysfunction; Modeling; Molecular; Multiple Sclerosis; Neurologic; Neurons; Oligodendroglia; Organ; Osmoregulation; Oxygen; Parasites; Pathogenesis; Pathologic; Pathology; Patients; Pericytes; Phenotype; Physiological; Property; Research; Sampling; Signal Pathway; Signal Transduction; Stimulus; Stroke; Testing; Therapeutic; Trees; Variant; Vasodilation; base; blood-brain barrier disruption; brain abnormalities; brain cell; brain endothelial cell; brain tissue; cell motility; cerebral microvasculature; deprivation; frontal lobe; gray matter; immunocytochemistry; microbial; monocyte; nervous system disorder; neuroAIDS; neurotropic; neurovascular unit; new therapeutic target; precision medicine; receptor; response; targeted treatment; transcriptome; vascular factor; white matter

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.

项目摘要 在各种神经系统疾病中，已经观察到大脑异常， 使用MRI和免疫组织学方法对脑区进行检测。其中包括患有 中风、小血管疾病、多发性硬化症和感染性疾病，如脑 疟疾（CM）。许多神经系统疾病包含潜在的血管成分。 脑血管病变似乎根据血管大小和特定脑区而不同， 血管驻留，包括灰质（GM）与白色血管驻留的差异 问题（WM）。这些不同的病理学在CM中尤其明显： 但不是GM。人们对这些差异究竟是什么、潜在的原因知之甚少 GM与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，包括转运蛋白，受体， 连接分子和细胞粘附分子。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 差异可能是造成不同的炎症和出血反应， 刺激，如微生物刺激，中风中的缺氧，或对 治疗学 在这个建议中，我们打算研究大脑血管系统的潜在差异 使用不同大脑区域的人脑样本， 结合体外BBB建模。我们建议比较A）全局表达式 大脑微血管的差异。此后，独特的血管标记， 将选择对某些脑区域特异的蛋白质，并确认它们在不同脑中的表达 地区B）使用体外BB B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，这一建议将导致澄清血管的差异， 不同的大脑区域，并将提供不同的病理观察到的解释， 神经系统疾病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。