Development and application of tissue-directed medicinal resources based on biotechnology
基于生物技术的组织定向药用资源开发与应用
基本信息
- 批准号:12470503
- 负责人:
- 金额:$ 9.09万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2000
- 资助国家:日本
- 起止时间:2000 至 2002
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
For therapy of human genetic diseases, the research had been performed to establish the enzyme and gene replacement methods and to discover the medicinal resources for the selective tissue targeting affected with lysosomal enzyme deficiencies. During the term of project, new findings were obtained as follows :1. Protective protein/cathepsin A (PPCA) is a multifunctional glycoprotein that exhibits the protective effects on lysosomal neuraminidase (Neur) and β-galactosidase (β-Gal), and serine carboxypeptidase (cathepsin A ; Cath A) activity on a subset of neuropeptides including endothelin-1 (ET-1). Galactosialidosis (GS) is a human PPCA deficiency with autosomal recessive genetic trait, accompanied by the simultaneous decrease of these enzyme activities and multiple clinical manifestations including neurological abnormalities. Histochemical analysis of the autopsied GS brain against ET-1, one of the putative endogenous substrates of the Cath A, was performed. ET-1-like immunoreactivity … More in the neural cells with GS was demonstrated to increase abnormally.2. Simultaneous expression of ET-1 precursor protein and ET-B receptor cDNAs caused the accumulation of ET-1 in the GS fibroblastic cell line.3. PPCA gene disruption in a human astrocytoma cell line was performed using the targeting vector containing the drug-resistant gene cassette between the two loxP sequences. The cell line with one disrupted allele of PPCA gene was obtained.4. Homology modeling of human Neur was performed on the basis of X-ray structure of microbial neuraminidases. Structural effects of amino acid substitutions identified in human Neur deficiency (sialidosis) predicted that the domain in which some substitutions locate might contribute to the interaction with PPCA molecule.5. Sandhoff disease is a GM2-gangliosidoses caused by the genetic defect of the β-subunit of lysosomal β-hexosaminidase. In the gene-disrupted mice as the disease model were used to elucidate the pathogenesis and were found to express specifically some types of chemokine parallel to the accumulation of GM2-ganglioside in the brain. This phenomenon was considered to be applicable to develop novel cell replacement therapy.6. Novel apoptosis-inducing compounds were discovered from the synthetic key intermediates of the bioactive halichroline that has the inhibitory action on the induced-expression of vascular cell adhesion molecule (VCAM-1) on the human umbilical vascular endothelial cells (HUVEC). Less
在人类遗传性疾病的治疗中,人们一直在研究建立酶和基因替代方法,并为受溶酶体酶缺陷影响的选择性组织靶向寻找药物资源。在项目实施过程中,取得了以下新的研究成果:1.保护蛋白/组织蛋白酶A(PPCA)是一种多功能糖蛋白,其对溶酶体神经氨酸酶(Neur)和β-半乳糖苷酶(β-Gal)表现出保护作用,并且对包括内皮素-1(ET-1)在内的神经肽子集表现出丝氨酸羧肽酶(组织蛋白酶A ; Cath A)活性。半乳糖唾液酸沉积症(Galactosialidosis,GS)是一种具有常染色体隐性遗传特征的人类PPCA缺陷症,伴随着这些酶活性的同时降低和包括神经系统异常在内的多种临床表现。对尸检GS脑进行了针对ET-1(Cath A的推定内源性底物之一)的组织化学分析。ET-1样免疫反应性 ...更多信息 结果:1. GS处理的神经细胞中,GSH-Px活性异常增高.同时表达ET-1前体蛋白和ET-B受体cDNA可引起GS成纤维细胞系中ET-1的积聚.使用在两个loxP序列之间含有耐药基因盒的靶向载体在人星形细胞瘤细胞系中进行PPCA基因破坏。获得了PPCA基因一个等位基因缺失的细胞系.基于微生物神经氨酸苷酶的X射线结构进行了人神经元的同源性建模。在人类Neur缺陷症(唾液酸沉积症)中鉴定的氨基酸取代的结构效应预测了某些取代所在的结构域可能有助于与PPCA分子的相互作用. Sandhoff病是由溶酶体β-氨基己糖苷酶β-亚基的遗传缺陷引起的GM 2-神经节苷脂沉积症。在基因破坏的小鼠作为疾病模型被用来阐明发病机制,并发现特异性表达的某些类型的趋化因子平行于GM 2-神经节苷脂在脑中的积累。这种现象被认为适用于开发新的细胞替代疗法.从生物活性盐咯啉(halichroline)的合成关键中间体中发现了新的诱导凋亡的化合物,盐咯啉对人脐血管内皮细胞(HUVEC)上的血管细胞粘附分子(VCAM-1)的诱导表达具有抑制作用。少
项目成果
期刊论文数量(46)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ohsugi K., Kobayashi K., Itoh K., Sakuraba H., Sakuragawa N.: "Enzymatic corrections for cells derived from Fabry disease patients by a recombinant adenovirus vector."J. Hum. Genet.. 45. 1-5 (2000)
Ohsugi K.、Kobayashi K.、Itoh K.、Sakuraba H.、Sakurakawa N.:“通过重组腺病毒载体对法布里病患者来源的细胞进行酶校正。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
伊藤 孝司: "保護タンパク質/カテプシンAおよびリソソーム性シアリダーゼと遺伝性代謝異常症"生化学. 72. 1160-1164 (2000)
Takashi Ito:“保护蛋白/组织蛋白酶 A 和溶酶体唾液酸酶与遗传性代谢紊乱”《生物化学》72. 1160-1164 (2000)。
- DOI:
- 发表时间:
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- 影响因子:0
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- 通讯作者:
Midori Itoh: "Apoptosis-inducing activity of synthetic halichlorine intermediates"Bioorganic & Medicinal Chemistry Letters. 12. 2069-2072 (2002)
Midori Itoh:“合成卤氯中间体的细胞凋亡诱导活性”生物有机
- DOI:
- 发表时间:
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- 影响因子:0
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Kohji Itoh: "Novel missense mutations in the human lysosomal sialidase gene in sialisosis patients and prediction of structural alterations of mutant enzymes"Journal of Human Genetics. 47. 29-37 (2002)
Kohji Itoh:“唾液酸中毒患者中人类溶酶体唾液酸酶基因的新错义突变以及突变酶结构改变的预测”人类遗传学杂志。
- DOI:
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- 影响因子:0
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- 通讯作者:
Naganawa, Y., Itoh, K., Shimmoto, M., Kamei, S., Takiguchi, K., Doi, H., Nishizawa, Y., Kobayashi, T., Kamei, S., Pshezhetsky, A.V., Potier, M., Sakuraba, H.: "Molecular and structural studies of Japanese patients with sialidosis type 1."J. Hum. Genet.. 4
Naganawa, Y.、Itoh, K.、Shimmoto, M.、Kamei, S.、Takiguchi, K.、Doi, H.、Nishizawa, Y.、Kobayashi, T.、Kamei, S.、Pshezhetsky, A.V.、Potier
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- 影响因子:0
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ITOH Kohji其他文献
ITOH Kohji的其他文献
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{{ truncateString('ITOH Kohji', 18)}}的其他基金
Rational design of high functional biosupra and development of therapeutic evaluation system with disease models
高功能biosupra的合理设计及疾病模型治疗评价体系的开发
- 批准号:
17H04102 - 财政年份:2017
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of neoglycobiologics and application for drug discovery for lysosomal diseases
新糖生物制剂的开发及其在溶酶体疾病药物发现中的应用
- 批准号:
26293120 - 财政年份:2014
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Establishment of induced neurons (iN cells) derived from lysosomal disease patients involving neurological symptoms and elucidation of regulatory mechanism of neurodegeneration
建立源自涉及神经症状的溶酶体疾病患者的诱导神经元(iN细胞)并阐明神经变性的调节机制
- 批准号:
26670269 - 财政年份:2014
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Practicing Engineering Classes Incorporating Computer-Assisted Collaborative Learning
实践结合计算机辅助协作学习的工程课程
- 批准号:
24501164 - 财政年份:2012
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Discovery of novel compounds regulating traffic to lysosomes and application for development of therapeutics
调节溶酶体运输的新型化合物的发现及其在治疗药物开发中的应用
- 批准号:
24659262 - 财政年份:2012
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Development of neo-biologics targeted on protein-protein interaction sites
针对蛋白质-蛋白质相互作用位点的新生物制剂的开发
- 批准号:
23390140 - 财政年份:2011
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Learning Assistant System Providing Materials with Knowledge Relational Maps to Help Retrieval and a Work Place for Solving Problems in Collaboration to Promote Generalized Knowledge Usability
学习辅助系统提供材料知识关系图帮助检索和协作解决问题的工作场所促进广义知识可用性
- 批准号:
21500920 - 财政年份:2009
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Computer-Assisted Second Language Learning by Going Back and Fourth in a Collection of Layered Learning Materials for Formative Learning
通过在形成性学习的分层学习材料集中回顾和第四次计算机辅助第二语言学习
- 批准号:
15300285 - 财政年份:2003
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
A Study on Network Media Systems Assisting Life-Long learning in Collaboration
网络媒体系统辅助终身协作学习的研究
- 批准号:
12558014 - 财政年份:2000
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
A Study on Collaborative Learning Environment Assisting Learning by Teaching Problem-Solving Strategies to a Computer Agent
通过向计算机代理教授问题解决策略来辅助学习的协作学习环境的研究
- 批准号:
09558019 - 财政年份:1997
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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Elucidating the function of a protective protein in a novel in vitro reconstitution system for disaggregation of ubiquitinated amyloid fibrils
阐明保护蛋白在新型体外重构系统中用于解聚泛素化淀粉样蛋白原纤维的功能
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Apoj/Clusterin:A Protective Protein In Vascular Biology
Apoj/Clusterin:血管生物学中的保护蛋白
- 批准号:
6545619 - 财政年份:2002
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$ 9.09万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES ON HUMAN PROTECTIVE PROTEIN
人类保护蛋白的晶体学研究
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6586572 - 财政年份:2002
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Apoj/Clusterin:血管生物学中的保护蛋白
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6615795 - 财政年份:2002
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Apoj/Clusterin:A Protective Protein In Vascular Biology
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6776944 - 财政年份:2002
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CRYSTALLOGRAPHIC STUDIES ON HUMAN PROTECTIVE PROTEIN
人类保护蛋白的晶体学研究
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6658539 - 财政年份:2002
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Apoj/Clusterin:A Protective Protein In Vascular Biology
Apoj/Clusterin:血管生物学中的保护蛋白
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6923640 - 财政年份:2002
- 资助金额:
$ 9.09万 - 项目类别:
CRYSTALLOGRAPHIC STUDIES ON HUMAN PROTECTIVE PROTEIN
人类保护蛋白的晶体学研究
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6437490 - 财政年份:2001
- 资助金额:
$ 9.09万 - 项目类别: