New Ops:Vasc Leakage Inhibition Protects Against Anthrax Pleural Effusions &Edema
New Ops:Vasc Leakage Inhibition Protects Against Anthrax Pleural Effusions &Edema
批准号:
7645448
负责人:
Joanne Chan
金额:
$23.94万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-03-01 至 2009-02-28
关键词:
AcuteAdultAnthrax diseaseAntibioticsAttenuatedBiological AssayBlood VesselsCardiovascular PhysiologyCase StudyCaviaCessation of lifeChemicalsChestClinicalDataDefectDrainage procedureDyesEdemaEmbryoEndothelial CellsExtravasationHospitalsHumanImageInjection of therapeutic agentIntensive CareLifeLiquid substanceLungMeasuresMediastinumMembraneModelingMusNumbersOrganOryctolagus cuniculusPathway interactionsPhosphorylationPleuralPleural effusion disorderRattusSkinStagingTestingTherapeuticTimeTissuesToxic effectToxinVEGFR inhibitionVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth FactorsVascular PermeabilitiesZebrafishabstractingage relatedanthrax lethal factoranthrax toxinattenuationbevacizumabcancer therapyinhibitor/antagonistmaculanonhuman primateprotective effectresearch study
中文摘要
1. 摘要
英文摘要
1. Abstract
Human case studies have described pleural effusions and the presence of a widened mediastinum on
chest x-rays as the most common clinical features of anthrax disease. Of the 11 people who developed acute
anthrax disease in 2001, 6 survived due to the intensive care received at hospitals that included fluid drainage
from the lung, and treatment with antibiotics. Increased vascular permeability has been strongly implicated in
anthrax toxin induced tissue edema in a large number of mammalian models (non-human primates, rabbits,
guinea pigs, rats, mice). The importance of blood vessels and endothelial cells in anthrax toxicity has been
difficult to investigate due to the inability to observe progressive vascular changes without sacrificing the
mammalian host. Therefore, we developed the transparent zebrafish embryo as a model to facilitate live
imaging of anthrax lethal toxin action on intact blood vessels. We observed that lethal toxin induced increased
vascular permeability as an early consequence leading to progressive defects in cardiovascular function. Since
vascular permeability is regulated by the vascular endothelial growth factor, also called the vascular
permeability factor (VEGFNPF), we employed chemical inhibitors to block this pathway to reduce toxin effects,
achieving remarkable levels of attenuation. These data were confirmed using an established vascular
permeability assay in adult mouse skin microvasculature termed the Miles Assay. Here, inhibition of the
VEGFNPF pathway reduced lethal toxin induced vascular leakage as measured by a colorimetric dye. Since
the Fischer 344 rat is an established anthrax toxin model where vascular defects have been observed, we are
currently employing this model to test the hypothesis that blocking the VEGF pathway can yield protective
effects against lethal toxin action as measured by increased survival time. This model is extremely sensitive to
lethal toxin challenge, typically inducing death in about 45-60 minutes. In our experiments, we observe
vascular defects in multiple organs and extensive pleural effusions at late stages during toxin challenge.
Analysis of VEGFR phosphorylation levels in the lung demonstrated increased activation of this pathway post
toxin injection, suggesting that inhibitors of the VEGF pathway could attenuate toxin effects. Since anti-VEGF
therapies are already in clinical use for cancer therapy and for the treatment of age-related vascularized
macula degeneration, further testing of their usefulness as an anti-anthrax therapeutic could be expedited. This
approach may be combined with antibiotics or anti-toxins to increase the therapeutic window for the effective
treatment of anthrax disease.
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会议论文
Host Vascular Mechanism for Therapeutic Protection against Select Pathogens
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批准号:8923142
-
项目类别:
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资助金额:$44.4万
-
财政年份:2014
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负责人:Joanne Chan
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依托单位:
Host Vascular Mechanism for Therapeutic Protection against Select Pathogens
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批准号:8902303
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项目类别:
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资助金额:$44.4万
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财政年份:2014
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负责人:Joanne Chan
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依托单位:
Host Vascular Mechanism for Therapeutic Protection against Select Pathogens
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批准号:8521077
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项目类别:
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资助金额:$22.61万
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财政年份:2012
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负责人:Joanne Chan
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依托单位:
Host Vascular Mechanism for Therapeutic Protection against Select Pathogens
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批准号:8391488
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项目类别:
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资助金额:$24.67万
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财政年份:2012
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负责人:Joanne Chan
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依托单位:
New Ops - Vascular Leakage Inhibition Against Anthrax Pleural Effusions & Edema
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批准号:7942386
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项目类别:
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资助金额:$29.27万
-
财政年份:2009
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负责人:Joanne Chan
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依托单位:
Enhancer/suppressor screens for angiogenic signaling
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批准号:7066533
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项目类别:
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资助金额:$27.06万
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财政年份:2004
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负责人:Joanne Chan
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依托单位:
Enhancer/suppressor screens for angiogenic signaling
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批准号:6916580
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项目类别:
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资助金额:$27.68万
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财政年份:2004
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负责人:Joanne Chan
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依托单位:
Enhancer/suppressor screens for angiogenic signaling
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批准号:6830418
-
项目类别:
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资助金额:$32.86万
-
财政年份:2004
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负责人:Joanne Chan
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依托单位:
Enhancer/suppressor screens for angiogenic signaling
-
批准号:7407545
-
项目类别:
-
资助金额:$26.28万
-
财政年份:2004
-
负责人:Joanne Chan
-
依托单位:
Enhancer/suppressor screens for angiogenic signaling
-
批准号:7229537
-
项目类别:
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资助金额:$26.28万
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财政年份:2004
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负责人:Joanne Chan
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依托单位:
Attacking anthrax action by blocking receptor signaling
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批准号:6803588
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项目类别:
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资助金额:$34.2万
-
财政年份:2003
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负责人:Joanne Chan
-
依托单位:
Attacking anthrax action by blocking receptor signaling
-
批准号:6674603
-
项目类别:
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资助金额:$33.6万
-
财政年份:2003
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负责人:Joanne Chan
-
依托单位:
海外基金