Manipulation of Host Angiogenesis as a Therapeutic Strategy against Invasive Pulm
操纵宿主血管生成作为针对侵袭性肺结核的治疗策略
基本信息
- 批准号:7905095
- 负责人:
- 金额:$ 7.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2012-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdjuvantAmphotericin BAngiogenesis InhibitorsAngiopoietin-1Antifungal AgentsAspergillosisAspergillusAutopsyBiological AssayBlood VesselsCessation of lifeCyclophosphamideDisease ProgressionDown-RegulationFailureFibroblast Growth Factor 2Gene ExpressionGrowth FactorHematopoietic stem cellsHigh Pressure Liquid ChromatographyImmune systemImmunocompromised HostIn VitroInfarctionInfectionInterventionInvadedIschemiaLesionLinkLungMalignant NeoplasmsMeasuresMediator of activation proteinModelingMusMycosesNeutropeniaOutcomePatientsPenetrationPharmaceutical PreparationsPolymerase Chain ReactionReproduction sporesResistanceRoleSiteStem cell transplantSubcutaneous InjectionsSupportive careSurvival RateSuspension substanceSuspensionsTestingTherapeuticThrombosisTissue SurvivalTissuesVascular DiseasesVascular Endothelial Growth Factorsangiogenesisblood vessel occlusiondensityimprovedin vivomatrigelmortalityneovascularizationnovelpublic health relevancerespiratoryresponsesynergismtreatment effect
项目摘要
DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is an important cause of respiratory and disseminated infection in immunocompromised patients, and the most common cause of infectious pneumonic mortality in recipients of hematopoietic stem cell transplants. Mortality from IA remains unacceptably high despite the availability of novel antifungal agents. The poor efficacy of antifungal drugs against IA may be linked to the propensity of Aspergillus species to invade pulmonary blood vessels, causing intravascular thrombosis, tissue ischemia and infarction. This vasculopathy sequesters infected tissue, thereby limiting the delivery of antifungal agents to the site of infection. Furthermore, IA is associated with down-regulation of the expression of genes encoding for important mediators of angiogenesis, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), suggesting that the vascular response to IA is suppressed. We hypothesize that therapeutic administration of pro-angiogenic growth factors together with antifungal drugs will increase the survival rate in experimental IA by increasing the tissue concentrations of the antifungal drugs. In aim 1, we propose to assess the feasibility of treating IA with pro-angiogenic growth factors, alone or in combination with the antifungal drug amphotericin B (AMB). To that end, we will use two murine models of IA following induction of neutropenia with cyclophosphamide: (1) An acute pulmonary model, in which infection is established by intranasal instillation of a concentrated spore suspension; (2) A subacute model, in which myocutaneous infection is induced by subcutaneous injection of spore suspension. In each model, the following treatment groups will be assessed: VEGF, bFGF, VEGF plus bFGF, AMB, AMB plus VEGF, AMB plus bFGF, and AMB plus VEGF and bFGF. Two additional groups of mice will receive treatment with sunitinib, an inhibitor of angiogenesis, alone or in combination with AMB. Three types of endpoints will be assessed and compared among treatment groups: (1) Survival over a period of 7 days (pulmonary model only); (2) Tissue fungal burden, measured by quantitative polymerase chain reaction (qPCR); and (3) Angiogenesis at the site of infection, assessed in vivo in the myocutaneous model using the previously described matrigel assay, and in pulmonary tissue sections using microvessel density. In aim 2, we will determine the effect of treatment with VEGF and bFGF on the tissue concentration of AMB. AMB concentrations will be measured in pulmonary tissue and in matrigel plugs using high performance liquid chromatography, and compared between groups of mice receiving AMB alone and groups receiving AMB plus VEGF and/or bFGF. PUBLIC HEALTH RELEVANCE: Invasive aspergillosis is a major cause of sickness and death in patients with cancer and a weakened immune system. Despite the availability of new antifungal drugs and improved supportive care, mortality from these infections remains unacceptably high. We hypothesize that the occlusion of blood vessels in the course of invasive aspergillosis limits the penetration of antifungal drugs into infected tissue, and that treatment with growth factors that enhance the formation of new vessels might improve the outcome of this severe fungal infection.
描述(由申请人提供):侵袭性曲霉病(IA)是免疫功能低下患者呼吸道和播散性感染的重要原因,也是造血干细胞移植受者感染性肺炎死亡的最常见原因。尽管有新的抗真菌药物,IA的死亡率仍然高得不可接受。抗真菌药物对IA的不良疗效可能与曲霉属物种侵入肺血管的倾向有关,从而导致血管内血栓形成、组织缺血和梗死。这种血管病变隔离了感染的组织,从而限制了抗真菌剂向感染部位的递送。此外,IA与编码血管生成的重要介质(如血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(bFGF))的基因表达的下调相关,表明对IA的血管反应被抑制。我们假设,治疗性给药的促血管生成生长因子与抗真菌药物将通过增加抗真菌药物的组织浓度增加实验IA的存活率。在目标1中,我们建议评估促血管生成生长因子单独或与抗真菌药物阿朴霉素B(AMB)联合治疗IA的可行性。为此,我们将使用环磷酰胺诱导中性粒细胞减少症后的两种IA小鼠模型:(1)急性肺模型,其中通过鼻内滴注浓缩孢子悬浮液建立感染;(2)亚急性模型,其中通过皮下注射孢子悬浮液诱导肌肉皮肤感染。在每个模型中,将评估以下治疗组:VEGF、bFGF、VEGF + bFGF、AMB、AMB + VEGF、AMB + bFGF和AMB + VEGF + bFGF。另外两组小鼠将接受舒尼替尼(一种血管生成抑制剂)单独或与AMB联合治疗。将评估三种类型的终点并在治疗组之间进行比较:(1)7天内的生存期(仅肺模型);(2)通过定量聚合酶链反应(qPCR)测量的组织真菌负荷;和(3)使用先前描述的基质胶测定在肌皮模型中体内评估的感染部位血管生成,以及使用微血管密度在肺组织切片中评估的血管生成。在目标2中,我们将确定用VEGF和bFGF治疗对AMB的组织浓度的影响。使用高效液相色谱法测量肺组织和基质胶塞中的AMB浓度,并在单独接受AMB的小鼠组与接受AMB加VEGF和/或bFGF的小鼠组之间进行比较。公共卫生相关性:侵袭性曲霉病是癌症患者和免疫系统减弱患者生病和死亡的主要原因。尽管有新的抗真菌药物和改善的支持性治疗,这些感染的死亡率仍然高得令人无法接受。我们推测,在侵袭性曲霉病的过程中,血管闭塞限制了抗真菌药物渗透到受感染的组织中,并且用促进新血管形成的生长因子治疗可能会改善这种严重真菌感染的结果。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Candiduria in haematologic malignancy patients without a urinary catheter: nothing more than a frailty marker?
- DOI:10.1111/myc.12024
- 发表时间:2013-05-01
- 期刊:
- 影响因子:4.9
- 作者:Georgiadou, Sarah P.;Tarrand, Jeffrey;Kontoyiannis, Dimitrios P.
- 通讯作者:Kontoyiannis, Dimitrios P.
Concurrent lung infections in patients with hematological malignancies and invasive pulmonary aspergillosis: how firm is the Aspergillus diagnosis?
血液系统恶性肿瘤和侵袭性肺曲霉菌病患者并发肺部感染:曲霉菌诊断有多可靠?
- DOI:10.1016/j.jinf.2012.05.001
- 发表时间:2012
- 期刊:
- 影响因子:0
- 作者:Georgiadou,SarahP;Kontoyiannis,DimitriosP
- 通讯作者:Kontoyiannis,DimitriosP
Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses.
- DOI:10.1007/s10096-012-1720-9
- 发表时间:2013-01
- 期刊:
- 影响因子:4.5
- 作者:Georgiadou, S. P.;Sampsonas, F. L.;Rice, D.;Granger, J. M.;Swisher, S.;Kontoyiannis, D. P.
- 通讯作者:Kontoyiannis, D. P.
Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections in patients with cancer.
- DOI:10.1016/j.jinf.2011.11.002
- 发表时间:2012-01
- 期刊:
- 影响因子:28.2
- 作者:Chitasombat, Maria N.;Kofteridis, Diamantis P.;Jiang, Ying;Tarrand, Jeffrey;Lewis, Russell E.;Kontoyiannis, Dimitrios P.
- 通讯作者:Kontoyiannis, Dimitrios P.
Risk factors for early mortality in haematological malignancy patients with pulmonary mucormycosis.
- DOI:10.1111/myc.12101
- 发表时间:2014-01
- 期刊:
- 影响因子:4.9
- 作者:Lewis RE;Georgiadou SP;Sampsonas F;Chamilos G;Kontoyiannis DP
- 通讯作者:Kontoyiannis DP
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
DIMITRIOS P KONTOYIANNIS其他文献
DIMITRIOS P KONTOYIANNIS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('DIMITRIOS P KONTOYIANNIS', 18)}}的其他基金
Development of an acute myeloid leukemia murine model of invasive pulmonary aspergillosis to gain insights into the role of leukemia and its treatments in the pathobiology of aspergillosis
开发侵袭性肺曲霉病的急性髓系白血病小鼠模型,以深入了解白血病及其治疗在曲霉病病理学中的作用
- 批准号:
10524878 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Development of an acute myeloid leukemia murine model of invasive pulmonary aspergillosis to gain insights into the role of leukemia and its treatments in the pathobiology of aspergillosis
开发侵袭性肺曲霉病的急性髓系白血病小鼠模型,以深入了解白血病及其治疗在曲霉病病理学中的作用
- 批准号:
10622540 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Redirected T Cell Therapy to Cure Invasive Fungal Infections
重定向 T 细胞疗法治愈侵袭性真菌感染
- 批准号:
10396163 - 财政年份:2016
- 资助金额:
$ 7.7万 - 项目类别:
Redirected T Cell Therapy to Cure Invasive Fungal Infections
重定向 T 细胞疗法治愈侵袭性真菌感染
- 批准号:
9813828 - 财政年份:2016
- 资助金额:
$ 7.7万 - 项目类别:
Manipulation of Host Angiogenesis as a Therapeutic Strategy against Invasive Pulm
操纵宿主血管生成作为针对侵袭性肺结核的治疗策略
- 批准号:
7706744 - 财政年份:2009
- 资助金额:
$ 7.7万 - 项目类别:
相似海外基金
Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
- 批准号:
23K08213 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
- 批准号:
2881726 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Studentship
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
- 批准号:
10722146 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
- 批准号:
10935776 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
- 批准号:
10935796 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
- 批准号:
10935775 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
- 批准号:
10649041 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
- 批准号:
10735964 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别: