赤痢アメーバをモデルとした寄生虫ポリアミン生合成経路の新展開
Project/Area Number |
21K15427
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 49040:Parasitology-related
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Research Institution | The University of Tokyo |
Principal Investigator |
Jeelani Ghulam 東京大学, 大学院医学系研究科(医学部), 助教 (60468519)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2022)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | Entamoeba histolytica / Protozoan parasite / Polyamine / Drug development / Metabolisms / Drug developement |
Outline of Research at the Start |
Metabolic pathways and specific enzymes that are selectively present in pathogens and essential for survival are ideal targets for chemotherapy. The polyamine synthesis pathway has been proven to be rational useful target. The human parasite, Entamoeba histolytica,lacks the conventional enzymes involved in polyamine biosynthesis. However, our previous metabolome analysis revealed that this parasite produces polyamines and secretes them extracellularly. This study aims to elucidate a novel polyamine synthesis pathway that has evolved peculiar to this parasites.
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Outline of Annual Research Achievements |
Purification and complete characterization of two enzymes involved in polyamine biosynthesis pathway have been completed. Gene silencing and metabolome analysis of one polyamine biosynthesis pathway enzyme (Ornithine decarboxylase) in Entamoeba histolytica has been completed. In this project we have identified one polyamine pathway enzyme which is essential for parasite survival, and since human homologue was absent, therefore this enzyme emerged as a novel drug target candidate We are going to submit two manuscript one related to glycerol biosynthesis and other related to hexosamine biosynthesis pathway in E. histolytica in this fiscal year. Five manuscripts as a coauthor have been published in the last fiscal year.
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have optimized protein purification protocol using hydrophobic (Butyl-Toyopearl) and anion exchange (MonoQ) columns and enzymatic assay (spermidine synthase) using HPLC, unfortunately we failed to identify the enzyme activity in the amebic lysate. Our repeated attempts to create a transformant in which expression of novel polyamine pathway enzyme repressed by epigenetic gene silencing failed, suggesting the essentiality of the gene.
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Strategy for Future Research Activity |
To understand the physiological role of the novel polyamine pathway enzyme which we identified in this study we will try other gene knock out approaches. After transcriptional silencing we will perform phenotypic analysis, RNAseq analysis and then metabolome analysis. Establish high throughput assay platform for screening Utokyo Drug discovery initiative compounds to identify inhibitors against the novel essential enzyme of polyamine biosynthesis and to determine the frequency, novelty, and potency of compounds with antiamebic activity. Complete and submit manuscript for publication.
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Report
(2 results)
Research Products
(10 results)
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[Journal Article] Attenuation of In Vitro and In Vivo Virulence Is Associated with Repression of Gene Expression of AIG1 Gene in Entamoeba histolytica2023
Author(s)
Lozano-Mendoza J, Ramirez-Montiel F, Rangel-Serrano A, Paramo-Perez I, Mendoza-Macias C, Saavedra-Salazar F, Franco B, Vargas-Maya N, Jeelani G, Saito-Nakano Y, Anaya-Velazquez F, Nozaki T, Padilla-Vaca F
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Journal Title
Pathogens
Volume: 12
Issue: 3
Pages: 489-489
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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