2019 Fiscal Year Final Research Report
Disruption of mental health induced by changes in brain environment: molecular mechanism and application to treatment of PTSD
| Project/Area Number |
18K19756
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
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| Research Institution | Wakayama Medical University |
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Principal Investigator |
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Keywords | 腫瘍壊死因子レセプタースーパーファミリー / 血液―脳関門 / 心的外傷後ストレス障害 / 運動 / ストレス |
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| Outline of Final Research Achievements |
To investigate the localization of TROY ligand in the brain, we used a chimeric protein consisting of the extracellular domain of mouse TROY and the Fc portion of human IgG1 (TROY-Fc). Double-immunofluorescence staining revealed that TROY-Fc was localized in GFAP-positive perivascular cells, suggesting that TROY ligands may be produced in perivascular astrocytes. To further elucidate the role of TROY and its ligand in the CNS in vivo, we generated transgenic (TG) mice expressing TROY-Fc under CAG promoter, in which TROY-Fc neutralize TROY ligands. Western blot analysis showed that expression levels of SSeCKS were significantly lower in the hippocampus of TG mice compared with wild-type mice. Overexpression of TROY in an astrocytoma cell line revealed that TROY signaling induced the protein expression of SSeCKS. These results indicate that TROY signaling in astrocytes may be involved in the formation and maintenance of BBB through the regulation of SSeCKS.
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| Free Research Field |
健康科学、神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
血液-脳関門(BBB)の破綻は高度のストレス負荷による高次脳機能障害を惹起するだけでなく、脳血管障害やアルツハイマー病などの中枢神経疾患の発症や病状進展においても注目されている。本研究において、TROYがアストロサイトによるBBBの成熟や維持に関与している可能性を示唆したことは、TNFRスーパーファミリーの新たな機能を発見しただけでなく、TNFRスーパーファミリーがBBBの破綻による中枢神経疾患の発症の病態に重要な役割を担う可能性を示唆したという観点からも学術的意義が高い。将来的には、TROYのシグナル伝達を標的として脳内環境の修復を目指す分子標的療法の開発につながることも期待される。
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