2021/10/1 11:00～12:00 ZOOM 若手道場
WD9-1
教師なし学習による神経膠腫幹細胞分類法の確立と糖代謝特異性
Establishment of unsupervised classification algorithm for glioma stem cells and their characteristics in glycolysis
○岡野 雄士1, Yoshitaka Kase1, Hideyuki Okano1
1.Department of Physiology, School of Medicine, Keio University, 2.Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo
○Yuji Okano1, Yoshitaka Kase1, Hideyuki Okano1
1.Department of Physiology, School of Medicine, Keio University, 2.Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo
Glioblastoma (GBM), a primary malignant brain tumor, and which is characterized by proliferation due to glioma stem cell (GSC), is known to have divergent phenotypes that come from its heterogeneity at molecular, cellular, and clinical levels.
Even though numerous studies offered various potential therapies, a radical cure for the disease is yet to come, partially because of the obstacles below.
First, the definition of GSC is conceptual, and there is no concrete way to draw a clear line between GSCs and non-stem GBM cells. Although some genes have been reported as markers for GSC, there is no consensus on any of these.
Second, the heterogeneity of GBM makes it more challenging to find a comprehensive therapy that can target all types of GBM cells, and it shows strong resistance to conventional approaches.
In order to settle the historical struggles and to find a cure for it, we aimed at Warburg’s effect, pathological enhancement of anaerobic glycolysis in tumor cells, as a highly preserved feature among GBM cells. This phenomenon is responsible for initiating the nucleic acid synthesis pathway, the pentose phosphate pathway (PPP).
In this study, we established an unsupervised machine learning algorithm for distinguishing GSCs from other GBM cells. Furthermore, we found the expression of hexokinase (HK) isozymes highly corresponded with GBM stemness. We also found that GSCs had a unique expression pattern of HK isozymes, which differed from that of non-stem GBM cells.
Given that HK is an essential kinase for PPP initiation, further understanding of the relationship between GBM stemness and HK will provide a new insight on GBM’s cancer cell biology that will potentially enable a uniform therapy. | | 2021/10/1 11:00～12:00 ZOOM 若手道場
WD9-2
骨格筋萎縮はヘモペキシン分泌を増加させアルツハイマー病の認知障害発症を加速する
Skeletal muscle atrophy increases hemopexin secretion and accelerates the onset of cognitive impairment in Alzheimer&'s disease.
○長瀬 綸沙, Chihiro Tohda
富山大学 和漢医薬学総合研究所 神経機能学領域
○Tsukasa Nagase, Chihiro Tohda
Section of Neuromedical Science, Institute of Natural Medicine, University of Toyama
The establishment of early diagnosis and prevention of Alzheimer′s disease (AD) are required. There are many epidemiological studies on risk factors for AD, and the physical inactivity is one of them. Several muscle secretory factor “myokines” are reported to be increased by exercise, and a positive relationship is supposed between those myokines and cognitive improvement. However, no studies have directly shown that skeletal muscle atrophy affects the development of cognitive dysfunction. Therefore, this study aimed to elucidate phenomenon and the mechanism of accelerating the onset of AD by skeletal muscle atrophy. To prepare a disuse muscle atrophy model, bilateral hindlimbs were immobilized by putting into casts for 14 days. Presymptomatic young age of 5XFAD mice were used. 5XFAD mice reveal cognitive impairment after 16 weeks of age. Object recognition memory in casted 5XFAD mice was impaired after the 14-day casting although age matched wild-type mice and non-cast 5XFAD mice showed normal memory function. After the memory test, hindlimb skeletal muscles were isolated for organ culture. Conditioned media of each muscle was separated on 2D-PAGE. After that spots were analyzed by MALDI-TOF/MS. Hemopexin was significantly increased in conditioned media of casted muscle. Furthermore, hemopexin in the plasma and hippocampus was increased in casted 5XFAD mice. We supposed that secreted hemopexin from skeletal muscle reached and affected the brain. Continuous i.c.v. infusion of hemopexin for 14 days during presymptomatic period induced memory deficit in young 5XFAD mice and increased inflammatory gene expression in the hippocampus. This study indicates that hemopexin is probably muscle atrophy-driven myokine to accelerate AD onset. |
