Mechanisms underlying neural activity-dependent albumin transport across brain endothelium

**0*0*1*336*1918*alon.Friedman@dal.ca*15*4*2250*14.0***正常*0***FALSE**en-CA*JA*HE******/**样式定义*/*表。MsoNormal表*{mso-style-name：“表正常”；*mso-tstyle-rowband-size：0；*mso-tstyle-colband-size：0；*mso-style-noshow：是；*mso-style-first：99；*mso-style-Parent：“”；*mso-pAdding-alt：0 cm 5.4pt 0 cm 5.4pt；*mso-para-edge-top：0 cm；*mso-para-edge-right：0 cm；*mso-para-edge-Bottom：8.0pt；*mso-par-边距-Left：0 cm；*行高：107%；*mso-Page：寡妇-孤儿；*FONT-SIZE：11.0pt；*FONT-FAMILY：CALIBRI；*MSO-ASCII-FONT-FAMILY：CALIBRI；*MSO-ASCII-TIME-FONT：Minor-拉丁语；*MSO-HANSI-FONT-FAMILY：CALIBRI；*mso-hansi-theme-font:minor-latin；}****The*goal我的研究计划是了解*允许哺乳动物正常大脑功能的神经-血管单位内的复杂关系。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)，这是一个特殊的结构和功能界面*，将大脑与循环中可能会改变或干扰正常大脑活动的成分隔绝。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。这些脑损伤的特征在包括人类在内的几乎所有哺乳动物身上都能找到。我的实验室以前曾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内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碱性转化生长因子β受体结合，导致Smad2/3*磷酸化和特征性的转录反应。我们的研究表明，血清白蛋白穿过内皮屏障可能是一种新的、星形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。目前提案的主要目标是探索血清白蛋白通过脑内皮细胞运输的基本生物学机制(即血脑屏障是如何*被调节的)。利用体内成像、电生理记录和*组织学方法，我们将：表征在神经元激活期间，白蛋白通过啮齿动物大脑皮层血脑屏障外渗的动力学和运输机制(目标1)；*专门测试神经元活动在促进血清白蛋白*运输中的作用(目标2)；以及在体内测试白蛋白跨内皮运输在改变网络活性方面的作用(目标3)。这项拟议中的研究将通过揭示血管通透性调节的潜在机制以及皮质网络可塑性的这种动态变化的潜力，为大脑功能提供新的见解。***

* * 0* 0* 1* 336* 1918* alon.friedman@dal.ca* 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. ***