Internal environment of the developing brain

发育中大脑的内部环境

• 批准号: 7025603
• 负责人: NORMAN RUTHVEN SAUNDERS
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF MELBOURNE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025603
• 关键词: biotin; blood brain barrier; blood proteins; cerebrospinal fluid; choroid plexus; developmental neurobiology; dextrans; electron microscopy; inflammation; inulin; light microscopy; lipopolysaccharides; membrane permeability; opossums; radiotracer; sucrose; tight junctions

DESCRIPTION (provided by applicant): The brain develops in a local (internal) environment that is distinct from the rest of the embryo, but is also different from the adult. The composition of the fluids (brain extracellular fluid, ECF and cerebrospinal fluid, CSF) that form the internal environment of brain is controlled by mechanisms referred to collectively as "the blood-brain barrier". Recent work of the Pl's group suggests the route of entry from blood to brain via the CSF in the developing brain may be more important than a direct route across blood vessels, which in immature brain are few. The long term aim is to understand the nature of mechanisms that control the composition of the internal environment of developing brain and to determine properties of its contribution to specific features of brain development. An additional aim is to understand effects on brain development resulting from pathophysiological disturbances to barrier mechanisms. The proposals concentrate on two aspects of control of the developing brain's internal environment, one a normal property of brain barrier mechanisms and the other, pathophysiological changes in barriers properties due to an inflammatory response:(i) Definition of permeability mechanisms and pathways between blood, CSF and brain at very early stages of development. (ii) Studies of acute & long-term effects of simulated infectious inflammatory responses (evoked by injection of lipopolysaccharide, LPS) on brain barrier permeability at different stages of development and in adults. The studies will be in S. American opossums (Monodelphis domestica); they are born at a very early stage of brain development (equivalent to 13 day fetal rats). The permeability mechanisms and pathways to be studied are to proteins and small molecular weight (mw) polar molecules. Biotin (244 Da), biotin labelled probes (eg biotin dextran mw 3000Da) and proteins (albumin & fetal protein, fetuin) will be injected intraperitoneally at different postnatal (P) ages up P65 (postweaning young adult) and their distribution in CSF and brain examined by light and electronmicrosopy. Their transfer into CSF will be quantitated and compared with results with classical but non-visualizable permeability probes (radiolabelled sucrose & inulin). Similar experiments, will study the effects of an acute or chronic inflammatory response (induced by injection of LPS for different periods) on barrier permeability at different ages.

描述（由申请人提供）：大脑在局部（内部）环境中发育，与胚胎的其他部分不同，但也与成人不同。形成脑的内部环境的流体（脑细胞外液，ECF和脑脊液，CSF）的组成由统称为“血脑屏障”的机制控制。PI小组的最近工作表明，在发育中的大脑中，通过CSF从血液进入大脑的途径可能比穿过血管的直接途径更重要，而在未成熟的大脑中，穿过血管的直接途径很少。长期目标是了解控制发育大脑内部环境组成的机制的性质，并确定其对大脑发育特定特征的贡献。另一个目的是了解障碍机制的病理生理干扰对大脑发育的影响。这些建议集中在两个方面的发展中的大脑的内部环境的控制，一个是正常的性质的脑屏障机制和其他的，由于炎症反应的屏障性能的病理生理变化：（i）定义的渗透性机制和血液，CSF和大脑之间的通路在非常早期的发展阶段。(ii)研究模拟感染性炎症反应（由注射脂多糖（LPS）引起）对不同发育阶段和成人脑屏障通透性的急性和长期影响。这些研究将在S。美国负鼠（Monodelphis arctica）;它们出生在大脑发育的早期阶段（相当于13天的胎鼠）。渗透机制和途径要研究的是蛋白质和小分子量（mw）极性分子。 在出生后不同年龄（P65）（断奶后青年）腹腔注射生物素（244 Da）、生物素标记探针（如生物素葡聚糖分子量3000 Da）和蛋白质（白蛋白和胎蛋白、胎球蛋白），用光镜和电镜观察它们在脑脊液和脑中的分布。将对它们向CSF中的转移进行定量，并与经典但不可见的渗透性探针（放射性标记的蔗糖和菊粉）的结果进行比较。类似的实验将研究急性或慢性炎症反应（通过注射LPS不同时期诱导）对不同年龄的屏障渗透性的影响。

项目成果

Expression and localization of P2 nucleotide receptor subtypes during development of the lateral ventricular choroid plexus of the rat.

大鼠侧心室脉络丛发育过程中 P2 核苷酸受体亚型的表达和定位。

• DOI: 10.1111/j.1460-9568.2007.05562.x
• 发表时间: 2007
• 期刊: The European journal of neuroscience
• 作者: Johansson,PA;Burnstock,G;Dziegielewska,KM;Guida,E;McIntyre,P;Saunders,NR
• 通讯作者: Saunders,NR

Effect of minocycline on inflammation-induced damage to the blood-brain barrier and white matter during development.

米诺环素对发育过程中炎症引起的血脑屏障和白质损伤的影响。

• DOI: 10.1111/j.1460-9568.2007.05973.x
• 发表时间: 2007
• 期刊: The European journal of neuroscience
• 作者: Stolp,HB;Ek,CJ;Johansson,PA;Dziegielewska,KM;Potter,AM;Habgood,MD;Saunders,NR
• 通讯作者: Saunders,NR