The role of anti-apoptotic factor 14-3-3 in HIV-1-associated dementia (HAD) pathology : The implication for the therapy
| Project/Area Number |
17591044
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | The University of Tokushima |
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Principal Investigator |
YANO Mihiro The University of Tokushima, Institute for Enzyme Research, Associated Professor, 分子酵素学研究センター, 助教授 (40304555)
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| Co-Investigator(Kenkyū-buntansha) |
KIDO Hiroshi The University of Tokushima, Institute for Enzyme Research, Professor, 分子酵素学研究センター, 教授 (50144978)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | HIV-1-associated dementia (HAD) / 14-3-3 protein / Neuronal cell death / Blood-brain barrier (BBB) / Tight Junction / proteasome |
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| Research Abstract |
We have previously suggested that, in patients with HAD, 14-3-3 proteins might be reliable markers of the rate and amount of neural cell destruction, since they are present in the CSF of patients isoform specifically. On the other hands, the infiltration of HIV-1, such as by virus-infected macropharges, across the damaged blood-brain barrier (BBB) into the CNS and consequent neural apoptosis are the characteristic pathologic manifestation of HAD. In this study, we have examined the role of 14-3-3 proteins in these critical processes of HAD and clarified their mechanisms.
14-3-3 proteins regulate the gp120-mediated apoptosis in neural cells. We found that, among the various 14-3-3 isoforms, 14-3-3τ specifically up-regulated in the brain tissue of AIDS patients with HAD. Since the viral envelope glycoprotein, gp120, has been proposed as a prominent inducer of neuronal loss, we next focused on the role of 14-3-3τ in the apoptosis using in vitro model cell culture system. Gp120 induced the
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α-chemokine receptor-mediated cell death and increased the expression of 14-3-3τ in HUVEC. Treatment of the cells with dsRNA against 14-3-3τ enhanced the gp120-mediated dephosphorylation of Bad and its translocation into the mitochondria, accelerating the gp120-induced apoptosis. These data demonstrate that 14-3-3τ protects against cell death induced by gp120 by a negative regulation of the activity of Bad.
14-3-3 proteins regulate the gp120-mediated disruption of tight junction (TJ) between human brain microvascular endothelial cells (HBMEC). Since HBMEC, a major cellular component of the BBB, are the first neural cells to be exposed to blood-borne viral products/-infected cells, the disruption of the BBB integrity is closely relevant to the pathogenesis of HAD. Growing evidences have indicated that neurotoxic viral proteins, such as gp120 and Tat increase endothelial permeability to facilitate the passage of HIV-1 across the BBB. We found that, as a novel explanation for increased microvascular permeability, gp120 induces the degradation of TJ proteins, such as ZO-1 and ZO-2 by the proteasome in HBMEC and 14-3-3τ negatively regulates this process. These data are the first evidence that demonstrates the molecular properties of the BBB breakdown by gp120. Less
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Report
(3 results)
Research Products
(11 results)
