Exploitation of new therapies for HTLV-I-assotiated myelopathy
HTLV-I 相关脊髓病新疗法的开发
基本信息
- 批准号:14207031
- 负责人:
- 金额:$ 23.71万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (A)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2004
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In this research project, we have deeply improved our understanding for the pathogenesis of HTLV-I-associated myelopathy(HAM) and developed a hopeful therapy for the disease. It is an initial event that HTLV-I-infected cells infiltrate into the central nervous system for the development of HAM, where matrix metalloproteinase(MMP)-2 and -9 play an important role. We found that a selective MMP inhibitor specific for MMP-2 and -9, N-Biphenyl sulfonyl-phenylalanine hydroxamic acid(BPHA), significantly inhibited migration activity of CD4+ T lymphocytes (which are a main reservoir of HTLV-I) from HAM patients. This suggests that the compound is a candidate for a new therapy for HAM patients. We had identified many genetic factors which increase susceptibility for the disease, and we newly identified two genetic factors, polymorphism of interleukin-10 promoter, and the length of tandem repeat in MMP-9 promoter. Using these host genetic factors, we made a formula to predict the risk of the development of HAM. When we utilized it for HTLV-I asymptomatic carriers, the carriers with high risk values showed faint abnormalities on the neurological examination, suggesting that the formula is very useful for prediction of the prognosis. In a genetic analysis of HTLV-I, the ratio of non-synonymous change to synonymous change (dN/dS ratio) of HTLV-I gene was lower in HAM patients than in HTLV-I carriers, implying that viral replication is more effectively inhibited in HAM patients than in the carriers. Moreover, HAM patients with HLA-A^*02 had lower dN/dS ratio than those without HLA-A^*02, suggesting that HL-A^*02 has an inhibitory effect on viral replication. Additionally, an analysis of dN/dS ratio, cytotoxic T lymphocytes(CTL) epitopes and frequency of mutant virus demonstrated that CTL had antiviral pressure in vivo, however, a mutant virus did not predominate. Further studies are needed to establish a more effective therapy for HAM patients.
通过本研究项目,我们对HTLV-I相关性脊髓病(HAM)的发病机制有了更深入的认识,并开发了一种有希望的治疗方法。HTLV-1感染的细胞浸润中枢神经系统是HAM发生的起始事件,其中基质金属蛋白酶(MMP)-2和-9起重要作用。我们发现一种特异于MMP-2和MMP-9的选择性MMP抑制剂,N-联苯磺酰基-苯丙氨酸异羟肟酸(BPHA),显著抑制HAM患者的CD 4 + T淋巴细胞(HTLV-1的主要储存库)的迁移活性。这表明该化合物是HAM患者新疗法的候选者。我们已经确定了许多遗传因素,增加了疾病的易感性,我们新确定了两个遗传因素,白细胞介素-10启动子的多态性,和MMP-9启动子串联重复序列的长度。利用这些宿主遗传因素,我们建立了一个预测HAM发生风险的公式。当我们将其用于HTLV-I无症状携带者时,具有高风险值的携带者在神经系统检查中显示出微弱的异常,这表明该公式对于预测预后非常有用。在HTLV-I的遗传分析中,HAM患者中HTLV-I基因的非同义变化与同义变化的比率(dN/dS比率)低于HTLV-I携带者,这意味着HAM患者比携带者更有效地抑制病毒复制。此外,具有HLA-A^*02的HAM患者比不具有HLA-A^*02的HAM患者具有更低的dN/dS比率,表明HL-A^*02对病毒复制具有抑制作用。此外,dN/dS比值,细胞毒性T淋巴细胞(CTL)表位和突变病毒频率的分析表明,CTL在体内具有抗病毒压力,但突变病毒并不占优势。需要进一步的研究来为HAM患者建立更有效的治疗方法。
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Human t-cell lymphotropic virus type I (HTLV-I) - Related clinical and laboratory findings for HTLV-I-infected blood donors
- DOI:10.1097/00126334-200303010-00013
- 发表时间:2003-03-01
- 期刊:
- 影响因子:3.6
- 作者:Furukawa, Y;Kubota, R;Osame, M
- 通讯作者:Osame, M
The clinical and pathological features of peripheral neuropathy accompanied with HTLV-I associated myelopathy
- DOI:10.1016/s0022-510x(02)00279-4
- 发表时间:2003-01-15
- 期刊:
- 影响因子:4.4
- 作者:Kiwaki, T;Umehara, F;Osame, M
- 通讯作者:Osame, M
Nagai M, et al.: "Failure to detect HTLV type 1 DNA from HTLV type 1-seronegative patients with chronic progressive spastic paraparesis in Kagoshima"AIDS Res Hum Retroviruses.. 18(14). 1089-1090 (2002)
Nagai M 等人:“未能从鹿儿岛患有慢性进行性痉挛性截瘫的 HTLV 1 型血清阴性患者中检测到 HTLV 1 型 DNA”AIDS Res Hum 逆转录病毒.. 18(14)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Serum concentration and genetic polymorphism in the 5'-untraslated region of VEGF is not associated with susceptibility to HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected
HTLV-I 感染者中 VEGF 5-非翻译区的血清浓度和遗传多态性与 HTLV-I 相关脊髓病/热带痉挛性截瘫 (HAM/TSP) 的易感性无关
- DOI:
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:Saito M;et al.
- 通讯作者:et al.
Decreased human T lymphotropic virus type I(HTLV-I) provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopathy/tropical spastic paraparesis.
干扰素-α 治疗 HTLV-I 相关脊髓病/热带痉挛性截瘫后,人类 T 淋巴细胞病毒 I 型 (HTLV-I) 原病毒载量下降,T 细胞表型发生改变。
- DOI:
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:Saito M;et al.
- 通讯作者:et al.
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OSAME Mitsuhiro其他文献
OSAME Mitsuhiro的其他文献
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{{ truncateString('OSAME Mitsuhiro', 18)}}的其他基金
HAMの臨床病態・発症機序の解明並びに新治療法の開発に関する研究
阐明HAM临床病理和发病机制并开发新疗法的研究
- 批准号:
11470146 - 财政年份:1999
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Research on Pathomechanism and a novel treatment of HTLV-I-associated myelopathy (HAM)
HTLV-I相关性脊髓病(HAM)的发病机制及新疗法研究
- 批准号:
09470155 - 财政年份:1997
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Pathology and Molecular Evolution of HTLV in Asia
亚洲 HTLV 的病理学和分子进化
- 批准号:
07042008 - 财政年份:1995
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for international Scientific Research
Epidemiology and pathology of human retrovirus infection
人类逆转录病毒感染的流行病学和病理学
- 批准号:
06042013 - 财政年份:1994
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for international Scientific Research
Epidemiology and pathology of human retro virus infection.
人类逆转录病毒感染的流行病学和病理学。
- 批准号:
04042017 - 财政年份:1992
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for international Scientific Research
RESEARCH FOR THE PATHOMECHANISM, EPIDEMILOGY AND TREATMENTS FOR HAM AND HTLV-I RELATED DISORDERS.
火腿和 HTLV-I 相关疾病的发病机制、流行病学和治疗研究。
- 批准号:
03454219 - 财政年份:1991
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)
Research of Clinical Features and Pathomechanism of HAM
HAM的临床特点及发病机制研究
- 批准号:
62480208 - 财政年份:1987
- 资助金额:
$ 23.71万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)