血液脳関門 Blood-Brain Barrier
P1-2-23 神経細胞とグリア細胞が共存する新規In Vitro 血液脳関門モデルの開発 Development of in vitro blood-brain barrier model reflecting the function of neurovascular unit ○重本-最上由香里1, 干川和枝1, 三浦麻利衣2, 関野祐子1, 佐藤薫1 ○Yukari Shigemoto-Mogami1, Kazue Hoshikawa1, Marie Miura2, Yuko Sekino1, Kaoru Sato1 国立衛研・薬理1, 慶大・薬2 Divi Pharmacol, Natl Inst Hlth Sci, Tokyo1, Divi Pharm, Univ of Keio, Tokyo2 The blood-brain barrier (BBB) restricts the transport of substances between vasculature and brain, and BBB permeability is important data for the development of new drugs. The regulation of BBB permeability is correlated with the function of neurovascular unit (NVU) comprised of endothelial cells, pericytes, glial cells (astrocytes, microglia, etc.) and neurons. In this study, we tried to develop an in vitro BBB model reproducing the function of NVU. Firstly, we replaced astrocytes with the freshly cultured astrocytes in the commercially-available in vitro BBB model. The transendothelial electrical resistance (TEER) of BBB became higher and the permeability coefficient for NaF and EBA became lower, indicating that tight junctions became tighter. When we supplemented this model further with primarily-cultured microglia and neurons, especially decreased the permeability coefficient for NaF. These results suggest that the supplement the existing BBB model with NVU components improves the BBB barrier function and reproduce NVU function. Currently, we are investigating the BBB change under inflammatory condition using our new in vitro BBB model.	P1-2-24 成体マウスの脳室周囲器官における血管新生因子VEGFとNotchシグナリング VEGF and Notch signaling in angiogenic processes of adult mouse circumventricular organs ○鵜飼真璃1, 森田晶子1,2, 宮田清司1 ○Shinri Ukai1, Shoko Morita1,2, Seiji Miyata1 京都工芸繊維大院・応用生物学1, 奈良県立医大・医・第二解剖2 Dept of Appl Biol, Kyoto Inst of Tech, Kyoto, Japan1, Dept of Anat & Neurosci, Nara Med Univ, Nara, Japan2 The circumventricular organs (CVOs) lack the regular blood-brain barrier (BBB), although adult brains contain the blood-brain barrier that prevents free access of blood-derived substances to the brains by the tight junctions and maintains a specialized brain environment to preserve brain neurons from neutroxic molecules. Recently, we have found that continuous angiogenesis occurs in the CVOs of adult mouse brains together with gliogenesis and neurogeneses, including that vasculature of these brain regions are continuously reconstructed. The CVOs, such as the organum vasculosum of the lamina terminals (OVLT), subfornical organ (SFO), area postrema (AP), median eminence (ME), and neurohypophysis (NH), are brain areas that lack the blood-brain barrier (BBB) or tight junctions between endothelial cells. CVOs are able to access to circulating substances in blood and cerebrospinal fluids and thereby control osmolarity, blood pressure and brain immunoresponses. In the present study, we examined the expression of vascular endothelial growth factor (VEGF), most potent factor controlling angiogenesis, in the CVOs of adult mice. In the sensory CVOs, The expression of VEGF was high at neurons in the OVLT, SFO and AP, and at astrocytes in the AP. The numbers of VEGF-positive puncta were changed in response to osmotic stimulation. The localization of VEGF receptor 2 (VEGFR2) was high at endothelial cells. In addition, the localization of Delta like ligand 4 (DLL4), a ligand of Notch receptor, was high at pericytes in the sensory CVOs. The present study thus demonstrates that VEGF and DLL4-Notch signaling are concerned with continuous angiogenesis in the CVOs of adult mouse.
P1-2-25 ショウジョウバエをモデルとした血液脳関門関の制御機構の解析 Evolutionally conserved molecule regulates the integrity of Blood-Brain Barrier in Drosophila ○菅田浩司1, 島村理恵子1, 岡野栄之1 ○Hiroshi Kanda1, Rieko Shimamura1, Hideyuki Okano1 慶應大・医・生理学1 Dept Physiol, Keio Univ, Tokyo, Japan1 The blood brain barrier (BBB) is a cellular structure in the central nervous system (CNS) that restricts the molecular and cellular exchanges. The pathological disruption of BBB has been implicated in a wide spectrum of neurological disorders. Tight junctions (TJs) and transporters possess the central role to achieve the highly integrated mechanism of the BBB to strictly isolate the vertebrate CNS. TJs restrict the distance between adjacent epithelial cells lining the fine capillaries of the brain microvasculature to form a selective physical barrier. On the other hand, ATP binding cassette (ABC) transporters are known to be utilized for chemoprotection that actively expel lipophilic molecules. In spite of accumulating ex vivo models as well studies using rodents, it has still been less well understood how BBB function is established and maintained.In Drosophila melanogaster (fruit fly), BBB and epithelial paracellular barriers are provided by a type of glia, subperineurial glia (SPG), that are connected by septate junctions (SJs) that have functional and molecular similarities to vertebrate TJs. It has also been revealed that Drosophila also conserves the xenobiotic exclusion system, which is achieved by fly ABC transporter(s). We thus aimed to address the molecular mechanisms for regulating the BBB functions in vivo using powerful Drosophila genetics. To this end, we have performed a genome-wide RNAi screen to identify novel genes that are involved in the formation and maintenance of the BBB functions. We have identified several genes whose knock down shows the severe BBB dysfunction phenotype. We revealed that Drosophila BBB function depends on the function of an evolutionally conserved membrane protein, which regulates non-cell autonomous signal(s).

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