Mechanisms underlying neural activity-dependent albumin transport across brain endothelium

神经活动依赖性白蛋白跨脑内皮转运的机制

• 批准号: RGPIN-2018-05580
• 负责人: Friedman, Alon
• 金额: $ 2.11万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=651183
• 关键词: Mechanisms; underlying; neural; activity; dependent

* * 0* 0* 1* 336* 1918* [e-mail]* 15* 4* 2250* 14.0* * * * * *** * Normal* 0* * * * * false* false* false* * EN-CA* JA* HE* * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Table Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin-top:0cm;* mso-para-margin-right:0cm;* mso-para-margin-bottom:8.0pt;* mso-para-margin-left:0cm;* line-height:107%;* mso-pagination:widow-orphan;* font-size:11.0pt;* font-family:Calibri;* mso-ascii-font-family:Calibri;* mso-ascii-theme-font:minor-latin;* mso-hansi-font-family:Calibri;* mso-hansi-theme-font:minor-latin;}****The*goal of my research program is to understand the complex relationships within*the neuro-vascular unit that allow normal mammalian brain function. One aspect*of the neuro-vascular unit, that is the focus of my research, involves the*blood-brain barrier (BBB), a specialized structural and functional interface*that insulate the brain from components in the circulation that might otherwise*modify or interfere with normal brain activity. Indeed, brain injuries often*initiate a cascade of events that ultimately lead to (sometimes delayed) neurological*dysfunctions. These features of brain injury are found in essentially all*mammals including humans. My lab has previously studied the role of BBB*dysfunction, in the reorganization of the neuro-vascular network that occurs after*brain injuries. Using animal models for BBB opening in rodents, we discovered*the role of serum-derived albumin in reorganization of neuro-vascular networks*within the brain cortex. We showed that albumin binds to ALK5 transforming*growth factor beta (TGFβ) receptors on astrocytes, leading to Smad2/3*phosphorylation and a characteristic transcriptional response. Our studies*suggest transport of serum albumin across the endothelial barrier may be a*novel, astrocytic-mediated signaling mechanism for the generation of new*excitatory synapses and facilitation of synaptic connectivity. ***The*main goal of the current proposal is to explore the basic biological mechanisms*underlying the transport of serum albumin across brain endothelium (i.e., how*is the BBB regulated). Using in-vivo imaging, electrophysiological recordings and*histological methods we will: characterize the dynamics and transport mechanisms*underlying albumin extravasation through the BBB in the rodent cerebral cortex*during neuronal activation (Objective 1);*specifically test the role of neuronal activity in promoting serum albumin*transport (Objective 2); and test the*role of albumin trans-endothelial transport in modifications of network activity*in vivo (Objective 3). The proposed*research will offer new insights into brain function by revealing the*mechanisms underlying modulation of vascular permeability and the potential of*such dynamic changes in cortical network plasticity. ***

* * 0 * 0 * 1 * 336 * 1918 * alon. [e-mail] * 15 * 4 * 2250 * 14.0 ** 正常 * 0 * 假 * 假 * EN-CA * JA * HE ** * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** */*样式定义*/* table. MsoNormalTable *{mso-style-name："Table Normal";* mso-tstyle-rowband-size：0;* mso-tstyle-colband-size：0;* mso-style-noshow：yes;* mso-style-priority：99;* mso-style-parent："";* mso-padding-alt：0cm 5.4pt 0cm 5.4pt;* mso-para-margin-top：0cm;* mso-para-margin-right：0cm;* mso-para-margin-bottom：8.0pt;* mso-para-margin-left：0cm;* line-height：107%;* mso-pagination：widow-orphan;* font-size：11.0pt;* font-family：Calibri;* mso-asphalt-font-family：Calibri;* mso-asphalt-theme-font：minor-latin;* mso-hansi-font-family：Calibri;* mso-hansi-theme-font：minor-latin;}* 我的研究项目的目标是了解神经血管单元内的复杂关系，这些关系使哺乳动物的大脑功能正常。神经血管单位的一个方面，也是我研究的重点，涉及血脑屏障（BBB），一种专门的结构和功能界面，将大脑与循环中的成分隔离开来，否则可能会改变或干扰正常的大脑活动。事实上，脑损伤经常引发一连串的事件，最终导致（有时是延迟的）神经功能障碍。脑损伤的这些特征在包括人类在内的几乎所有哺乳动物身上都有发现。我的实验室以前研究过血脑屏障功能障碍在脑损伤后神经血管网络重组中的作用。利用啮齿类动物血脑屏障开放的动物模型，我们发现了血清来源的白蛋白在大脑皮层神经血管网络重组中的作用。我们发现，白蛋白与星形胶质细胞上的ALK 5转化 * 生长因子β（TGF β）受体结合，导致Smad 2/3 * 磷酸化和特征性转录反应。我们的研究表明血清白蛋白通过内皮屏障的转运可能是一种新的星形胶质细胞介导的信号机制，用于产生新的兴奋性突触和促进突触连接。* 当前提案的 * 主要目标是探索血清白蛋白跨脑内皮转运的基本生物学机制 *（即，* BBB是如何调节的）。使用体内成像、电生理记录和 * 组织学方法，我们将：描述神经元激活期间白蛋白通过啮齿动物大脑皮层 * 血脑屏障外渗的动力学和转运机制 *（目的1）;* 特异性测试神经元活性在促进血清白蛋白 * 转运中的作用（目标2）;并测试白蛋白跨内皮转运在体内网络活性改变中的作用（目标3）。这项拟议中的研究将通过揭示血管渗透性调节的潜在机制以及皮层网络可塑性动态变化的潜力，为大脑功能提供新的见解。***