Mechanisms underlying neural activity-dependent albumin transport across brain endothelium

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* * 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. ***