Glioma-Astrocyte Vascular Interactions

胶质瘤-星形胶质细胞血管相互作用

• 批准号: 8630567
• 负责人: HARALD W SONTHEIMER
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630567
• 关键词: Animal Disease Models; Animal Model; Arachidonic Acids; Astrocytes; Basal lamina; Behavior; Biology; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Bradykinin; Brain; Cells; Cerebrum; Chronic; Coupling; Disease; Environment; Enzymes; Excision; Extracellular Matrix; Future; Glioma; Grant; Growth; Image; Immune; In Situ; Invaded; Malignant neoplasm of brain; Nerve; Nutrient; Operative Surgical Procedures; Pathway interactions; Photons; Physiology; Primary Brain Neoplasms; Prostaglandins; Regulation; Research; Role; Shunt Device; Signal Transduction; Smooth Muscle Myocytes; Structure; Testing; Therapeutic Intervention; Tight Junctions; Vascular Endothelial Cell; Vasoconstrictor Agents; angiogenesis; clinically relevant; effective therapy; in vivo; insight; multi-photon; novel; public health relevance; receptor; tumor; white matter

Project Summary/Abstract: Primary brain tumors, gliomas, have thus far evaded effective treatment making them a tremendous challenge clinically. This is in part due to the unusual ability of gliomas to infiltrate surrounding brain making surgical resection difficult. Tumor cells can move through the brain parenchyma, following white matter tracts or along blood vessels. Ultimately many glioma cells associate with blood vessels, presumably to gain enhanced access to nutrients. In a recent study, we show that glioma cells are attracted to cerebral vessels by responding to bradykinin which is produced by vascular endothelial cells. Once associated with blood vessels, glioma cells co-opt the vasculature and eventually induce vessel sprouting and angiogenesis. Understanding how gliomas alter the physiology of the existing cerebral vasculature is the primary objective of this grant. We hypothesize that the vascular association provides an intrinsic advantage and that gliomas actively regulate the behavior of the associated blood vessel. More specifically we hypothesize that (1) vessel associated glioma cells displace astrocytic endfeet from the blood vessels; (2) this disrupts normal astrocyte-vascular coupling as astrocyte-derived vasoactive molecules fail to reach vascular smooth muscle cells; (3) displacement of astrocytic endfeet leads to a breakdown of the blood-brain barrier; and (4) once attached to vessels, glioma cells actively regulate vascular tone through the release of vasoactive compounds. These hypotheses will be tested using a clinically relevant animal model of glioma employing a combination of single- and multi-photon imaging studies in situ and in vivo. These studies have the potential to elucidate novel ways to interfere with the destructive biology of these deadly tumors in the future.

项目摘要/摘要： 迄今为止，原发性脑肿瘤、神经胶质瘤尚未得到有效治疗，这使得它们成为一种巨大的癌症。 临床上的挑战。这部分是由于神经胶质瘤具有异常的浸润周围大脑的能力 使手术切除变得困难。肿瘤细胞可以穿过脑实质，如下 白质束或沿着血管。最终许多神经胶质瘤细胞与血管相关， 大概是为了更好地获取营养。在最近的一项研究中，我们表明神经胶质瘤细胞 通过响应血管内皮细胞产生的缓激肽而被脑血管吸引 细胞。一旦与血管相关，神经胶质瘤细胞就会选择血管系统并最终诱导 血管萌芽和血管生成。了解神经胶质瘤如何改变神经胶质瘤的生理机能 现有的脑血管系统是这笔赠款的主要目标。我们假设 血管关联提供了内在优势，神经胶质瘤积极调节行为 相关血管。更具体地说，我们假设（1）血管相关神经胶质瘤 细胞将星形胶质细胞末端从血管中移出； (2) 这会破坏正常的星形胶质细胞血管 由于星形胶质细胞衍生的血管活性分子无法到达血管平滑肌细胞而发生偶联； (3) 星形胶质细胞末足的移位导致血脑屏障的破坏； (4) 一次 神经胶质瘤细胞附着在血管上，通过释放血管活性物质积极调节血管张力 化合物。这些假设将使用临床相关的神经胶质瘤动物模型进行测试 采用原位和体内单光子和多光子成像研究的结合。这些 研究有可能阐明干扰这些破坏性生物学的新方法 未来致命的肿瘤。