若手道場 グループＡ
Wakate Dojo group A |
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| 2020/9/11 13:30～13:45 オンデマンドA-1
WD1 【演題取消】
| | 2020/9/11 13:50～14:05 オンデマンドA-1
WD2
APLP1の哺乳類にのみ見られるヘパリンとの相互作用はシナプス間隙での自己二量体化を促進する
Unique interaction of mammalian APLP1 and heparin may promote self-dimerization at synaptic cleft
*小野寺 航1、朝日 透2,3、澤村 直哉3,4
1. 早稲田大学先進理工学研究科、2. 早稲田大学理工学術院、3. 早稲田大学ナノ・ライフ創新機構、4. 早稲田大学グリーン・コンピューティング・システム研究機構
*Wataru Onodera1, Toru Asahi2,3, Naoya Sawamura3,4
1. Waseda university, school of Advanced Science and Engineering, 2. Waseda university, faculty of Science and Engineering, 3. Waseda university, Research Organization for Nano & Life Innovation, 4. Waseda university, Green Computing Systems Research Organization
APP (Amyloid precursor protein) family is comprised of APP, APP-like protein (APLP) 1, and APLP2; when mutated, turns to be risk factors of multiple neurodegenerative diseases including Alzheimer's disease. APP family are known to present synaptogenic function especially during the adulthood, essential for maintenance of synapse network. The function is mediated by intercellular dimerization of APP family at synaptic cleft promoted by binding of metal ions, heparins, and extracellular proteins. There, APLP1 shows the highest efficiency of dimerization through unknown molecular mechanism resulting in more prominent synaptogenic function compared to APP and APLP2. Here, based on docking simulation, we show heparin binding to APLP1 may explain the accelerated dimerization rate. Importantly, heparin binds to novel protein surface of heparin binding domain of E1 in APLP1 shown by docking simulation. Interestingly, the surface was acquired at common ancestor of mammalian APLP1 and simultaneously, tends to have lost existing heparin binding motif which are still present in non-mammalian APLP1 and the other APP family. These results suggest unique heparin-induced dimer structure of mammalian APLP1, possibly explaining the observed efficient dimerization in previous reports. Furthermore, mammalian-specific synapse molecular feature may partially be defined by the rapid evolution towards heparin of APLP1. In the presentation, we will discuss on evolutionary mechanism of APLP1 acquiring novel heparin binding surface and subsequent effects on strengthening synaptic network of mammal. | | 2020/9/11 14:10～14:25 オンデマンドA-1
WD3
脊柱管狭窄に伴う慢性疼痛発症における脊髄後角アストロサイトの役割
Chronic pain of the lower extremity following compression of the upper spinal cord involves STAT3-dependent reactive astrocytes and interleukin-6
*大野 瑛明1,2、津田 誠2、中島 康晴1
1. 九州大学大学院医学研究院 整形外科、2. 九州大学大学院薬学研究院 ライフイノベーション分野
*Teruaki Ono1,2, Makoto Tsuda2, Yasuharu Nakashima1
1. Dept. of. Orthop. Surg., Graduate School of Medical Sciences, Kyushu University, 2. Dept. of. Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University
Chronic pain is a major symptom of spinal disorders such as spinal canal stenosis. A major cause for this pain is the compression of the spinal cord. While the compression itself directly affects pain signaling in the SDH, there are also many cases that the compressed segment of the spinal cord does not correspond to peripheral regions with chronic pain. However, its underlying mechanism remains unknown. The present study investigated this using a mouse model of SCC in which mechanical pain of the hindpaws was developed following the compression of boundary segments between the thoracic and lumbar cord. We found that SCC induced activation of astrocytes in the compressed SDH (but not L4 segment of SDH that corresponds to the hindpaws) and activated signal transducer and activator of transcription 3 (STAT3). Suppressing reactive astrocytes by expressing a dominant negative form of STAT3 (dnSTAT3) in the compressed SDH prevented mechanical pain. We further found that in the compressed SDH, expression of interleukin (IL)-6 was also upregulated, which was inhibited by astrocytic expression of dnSTAT3. Moreover, intrathecal administration of a neutralizing antibody for IL-6 reversed the SCC-induced pain hypersensitivity. These findings suggest that astrocytic STAT3 and IL-6 in the compressed SDH are involved in chronic pain of the lower extremity and may provide a target for treating chronic pain associated with SCC such as spinal canal stenosis. | | 2020/9/11 14:30～14:45 オンデマンドA-1
WD4
高血圧性緑内障はP2Y1受容体の機能障害によって誘導される
Hypertensive glaucoma is induced by impairment of P2Y1 receptor function
*濱田 健太郎1、篠﨑 陽一1,2、行方 和彦3、大野 伸彦4,5、瀬川 高弘6、原田 高幸3、柏木 賢治7、小泉 修一1,2
1. 山梨大・院医・薬理、2. 山梨大・脳免疫センター、3. 公益財団法人東京都医学総合研究所 疾患制御研究分野、4. 生理学研究所 分子細胞生理研究領域、5. 自治医科大医学部 解剖学講座組織学部門、6. 山梨大・総合分析実験センター、7. 山梨大・院医・眼科
*Kentaro Hamada Hamada1, Yoichi Shinozaki1,2, Kazuhiko namekata3, nobuhiko ohno4,5, takahiro segawa6, Takayuki Harada3, kenji kashiwagi7, schuichi Koizumi1,2
1. Dept. Neuropharmacol., Interdiscip. Grad. Sch. Med. Univ. Yamanashi, 2. Interdiscip. Brain-Immune Research Center , 3. Vis. Res. Project, Tokyo Metr. Inst. Med. Sci. , 4. Div. Ultrasct.Res., Natl. Inst. Physiol. Sci. , 5. Dept. Anat., Jichi Med. Univ. , 6. Cent. Life. Sci. Res. Univ. Yamanashi , 7. Dept. Ophthalmol., Interdiscp. Grad. Sch. Med. Univ. Yamanashi
Glaucoma is second leading cause of blindness worldwide. Blindness in glaucoma is caused by degeneration of retinal ganglion cells (RGCs). Although one of the most studied risk factors is an elevated intraocular pressure (IOP), the molecular mechanisms have not fully been clarified. We focused on purinergic signaling because glaucoma patients show elevated IOP associated with high ATP level in their aqueous humor (AH). Here we report that P2Y1 receptor is essential for IOP reduction and its dysregulation causes hypertensive glaucoma-like phenotypes. When we activate P2Y1 receptor by instillation of MRS2365, a selective agonist for P2Y1 receptor, IOP in wild-type (WT) mice was significantly decreased, which disappeared in P2Y1 receptor deficient (P2Y1KO) mice. We then investigated spatial expression patterns of P2Y1 receptor. Immunohistochemical analysis revealed that P2Y1 receptor was dominantly expressed in the ciliary body and the angle tissue including trabecular meshwork and Schlemm's canal, essential for AH production and draining, respectively. To further validate functional expression of P2Y1 receptor in these tissues, we performed Ca2+ imaging. MRS2365 evoked intracellular Ca2+ transients in ciliary body, trabecular meshwork and Schlemm's canal. We next measured basal IOP levels and found that P2Y1KO mice showed significantly higher IOP levels than WT mice, indicating its contribution to basal level of IOP. Quantitative analysis Rbpms -positive signals revealed that number of RGCs in P2Y1KO mice was significantly lower than that in WT in the middle age (12 months old) but not in the young adult (3 months old). Supporting this observation, number of apoptotic RGCs was significantly increased in the middle-aged P2Y1KO mice. Associating with RGC damages, RGC-mediated visual function was significantly impaired in the middle-aged P2Y1KO mice. Taken together, our results demonstrated that (1) P2Y1 receptor activation reduces IOP; (2) loss-of-function of P2Y1 receptor results in elevation of basal IOP and (3) P2Y1KO mice show hypertensive glaucoma-like phenotypes. | |
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