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Brain Barriers ID: Identifying and detailing the molecular mechanisms regulating integrity and immune function of the brain barriers

English title Brain Barriers ID: Identifying and detailing the molecular mechanisms regulating integrity and immune function of the brain barriers
Applicant Engelhardt Britta
Number 189080
Funding scheme Project funding (Div. I-III)
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2019 - 30.09.2023
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Immunology, Immunopathology

Keywords (9)

microfluidics; cellular junctions; immune cell trafficking; endothelial antigen-presentation; adhesion molecules; blood-brain barrier; multiple sclerosis; experimental autoimmune encephalomyelitis; blood-cerebrospinal fluid barrier

Lay Summary (German)

Lead
Brain Barriers ID
Lay summary
Multiple Sklerose (MS) ist die häufigste entzündliche Erkrankung des Zentralnervensystems (ZNS) bei jungen Erwachsenen und führt ohne Behandlung zu irreversiblen und schweren Behinderungen. Obwohl MS als T-Zell-vermittelte Autoimmunerkrankung gilt, sind Ätiologie und Pathologie nicht vollständig geklärt. Störung der Blut-Hirn-Schranke (BBB) als auch vermehrte Einwanderung von Immunzellen in das ZNS kennzeichnen die MS-Pathogenese und können im Tiermodell, experimentelle autoimmune Enzephalomyelitis (EAE) nachgestellt werden. Medikamentöse Blockade der Immunzellwanderung in das ZNS ist eine erfolgreiche Behandlung der MS, wird jedoch von zum Teil schwerwiegenden Nebenwirkungen begleitet und ist in der progressiven Phase der MS nicht mehr wirksam. 
Es besteht daher die Notwendigkeit, die Sicherheit der vorhandenen Therapieansätze zu erhöhen und neue Therapieansätze für die progressive MS zu entwickeln.  

Die Blut-Hirn Schranke wird durch hochspezialisierte Endothelzellen, welche die Gefässwand auskleiden, etabliert. Wir haben beobachtet, dass manche Immunzellen diese Endothelzellbarriere zwischen den Endothelzellen, also durch deren Zellkontakte durchbrechen, andere jedoch eine Pore durch den Endothelzellkörper „bohren“ und durch diese Pore den Blutkreislauf verlassen. Ein Teil des Projektes Brain Barriers ID zielt darauf hin zu verstehen, warum es diese zwei Wege der Immunzellpassage durch die BHS gibt, welche Immunzellen welchen Weg benutzen und welche Mechanismen dafür verantwortlich sind.  

Ausserdem haben wir beobachtet, dass manche Immunzellen über den Plexus Choroideus in das ZNS einwandern können. Der Plexus Choroideus ist eine Struktur, welche die Gehirnflüssigkeit – den Liquor - produziert und direkt in die mit Liquor gefüllten Räume des Gehirns hineinragt. Das Gewebe des Plexus Choroideus wird vom Liquorraum durch die Blut-Liquor Barriere (BLB) getrennt. Wir möchten herausfinden, ob und wenn ja welche Immunzellen die Blut-Liquor Schranke überwinden können, um direkt in den Liquorraum des ZNS zu gelangen.

Ob sich die im Tiermodell beobachteten Mechanismen auf die MS übertragen lassen, wollen wir abschliessend in Zellkulturmodellen der menschlichen BHS und BLB, welche wir aus Stammzellen von MS Patienten und gesunden Probanten etabliert haben, untersuchen.  

 

Mit den Kenntnissen aus Brain Barriers ID hoffen wir neue Zielstrukturen zu definieren, welche es erlauben i) die Sicherheit aktueller MS Therapien zu verbessern, ii) die Immunzellwanderung in das ZNS zu normalisieren und iii) die Funktion der BHS zu stabilisieren, um somit auch die Behandlung der progressiven MS oder anderer neurodegenerativer Erkankungen mit BHS Störungen zu ermöglichen.  
 

 

Direct link to Lay Summary Last update: 03.10.2019

Responsible applicant and co-applicants

Employees

Publications

Publication
Wnt signaling mediates acquisition of blood–brain barrier properties in naïve endothelium derived from human pluripotent stem cells
Gastfriend Benjamin D, Nishihara Hideaki, Canfield Scott G, Foreman Koji L, Engelhardt Britta, Palecek Sean P, Shusta Eric V (2021), Wnt signaling mediates acquisition of blood–brain barrier properties in naïve endothelium derived from human pluripotent stem cells, in eLife, 10, 1.
Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier
Castro Dias Mariana, Odriozola Quesada Adolfo, Soldati Sasha, Bösch Fabio, Gruber Isabelle, Hildbrand Tobias, Sönmez Derya, Khire Tejas, Witz Guillaume, McGrath James L., Piontek Jörg, Kondoh Masuo, Deutsch Urban, Zuber Benoît, Engelhardt Britta (2021), Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier, in Journal of Cell Science, 134(8), 1.
Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver
Baier Felix Alexander, Sánchez-Taltavull Daniel, Yarahmadov Tural, Castellà Cristina Gómez, Jebbawi Fadi, Keogh Adrian, Tombolini Riccardo, Odriozola Adolfo, Dias Mariana Castro, Deutsch Urban, Furuse Mikio, Engelhardt Britta, Zuber Benoît, Odermatt Alex, Candinas Daniel, Stroka Deborah (2021), Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver, in Cellular and Molecular Gastroenterology and Hepatology, 12(2), 745-767.
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Associated projects

Number Title Start Funding scheme
170131 Anatomical routes and molecular mechanisms of T cell migration across the brain barriers 01.10.2016 Project funding (Div. I-III)
198524 Cryo-focused ion beam scanning electron microscope to prepare cells for visualising their molecular architecture by electron cryo-tomography 01.11.2021 R'EQUIP

Abstract

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults and if untreated leads to irreversible and severe disability. Although MS is considered a T-cell mediated autoimmune disease, its etiology and pathology are not fully understood. Focal blood-brain barrier (BBB) breakdown and increased immune cell trafficking into the CNS are early hallmarks of MS pathogenesis and can be modeled in its animal correlate, experimental autoimmune encephalomyelitis (EAE). Therapeutic targeting of immune cell trafficking into the CNS has proven beneficial for the treatment of early relapsing-remitting MS but comes with rare severe side effects like progressive multifocal leukoencephalopathy (PML) and is no longer effective once patients have entered the progressive phase of the disease. BBB abnormalities persist in progressive MS. There is thus an unmet need to improve the safety of current therapies targeting immune cell trafficking to the CNS and to explore novel therapeutic options to restore brain barriers integrity. In our efforts to understand the molecular mechanisms involved in BBB breakdown and the mechanisms regulating T-cell trafficking to the CNS, we have made a number of quite unexpected observations: We found that i) the tight junction (TJ) sealing proteins, claudin-1 and claudin-3, are not expressed at the BBB; that ii) impaired BBB junctional integrity favors transcellular over paracellular T-cell diapedesis; that iii) endothelial antigen-presentation reduces CD8 T-cell diapedesis across the BBB, and that iv) T-cell invasion from the choroid plexus stroma into the brain parenchyma may not require crossing the epithelial blood-cerebrospinal fluid barrier (BCSFB). Our observations highlight that the molecular mechanisms regulating impaired brain barrier function during neuroinflammation are distinct from those, regulating T-cell entry into the CNS. This sets the stage of the present research proposal Brain Barriers ID that aims to identify and detail the molecular mechanisms regulating the integrity versus the immune function of the brain barriers. Employing in vivo models of Th1, Th17 and CD8 T-cell mediated autoimmune CNS inflammation, we will make use of the power of single cell RNAseq transcriptomics of the brain barriers to identify the transcriptional basis of the focal brain barrier changes observed in autoimmune neuroinflammation. To detail identified targets in regulating brain barriers integrity versus immune function, we will use our in vitro models of the BBB and the BCSFB combined with in vitro and in vivo live cell imaging technologies of the brain barriers. Specific Aim 1 will ID the mechanisms regulating BBB integrity versus CD4 T-cell diapedesis across the BBB with a first focus on understanding the role of tricellular junctions. Specific Aim 2 will ID the mechanisms regulating BBB integrity versus CD8 T-cell trafficking across the BBB aiming to first explore if endothelial antigen-presentation induces CD8 T-cell mediated BBB disruption. Specific Aim 3 will ID the mechanisms regulating BCSFB integrity versus CNS entry of Th17 cells via the ChP, first exploring the existence of a potential T-cell escape route avoiding the BCSFB at the base of ChP. Translation to MS is implemented in Specific Aim 4, which will make use of MS-patient sourced stem-cell derived in vitro brain barrier models to ID the mechanisms regulating brain barriers permeability versus T-cell diapedesis in man. With Brain Barriers ID we expect to create unique knowledge on the molecular mechanisms mediating focal brain barriers dysfunction versus dysregulated T-cell trafficking across the brain barriers during CNS autoimmune neuroinflammation. Identification of new targets for therapeutic improvement of brain barriers integrity versus immune function will allow to improve the safety of current therapeutic schemes blocking CNS entry of immune cell in MS and bears the hope for developing novel therapeutic strategies aiming to diagnose and restore brain barrier integrity in the treatment of progressive MS and other neurodegenerative disorders.
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