NOS2 and arginase in visceral leishmaniasis-FIRCA supplement
内脏利什曼病中的 NOS2 和精氨酸酶 - FIRCA 补充剂
基本信息
- 批准号:7758284
- 负责人:
- 金额:$ 3.38万
- 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:2009-01-15 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:AchyroclineAddressAnimal ModelAnimalsAntigensAreaBiologyCCL17 geneCCL22 geneCCL3 geneCessation of lifeChronicClinicalCollaborationsColombiaCutaneousCutaneous LeishmaniasisDiseaseDisease ResistanceDisease susceptibilityEpidemicEpidemiologic StudiesFosteringFoundationsGenesGrantHamstersHealedHumanHypersensitivity skin testingImmune responseImmunityIn VitroIndiaIndividualInfectionInterleukin-10Interleukin-13Interleukin-4InvestigationLeishmaniaLeishmaniasisMacrophage ActivationMarriageMediatingMetabolic PathwayMilitary PersonnelModelingMucocutaneous leishmaniasisMusNOS2A geneNational Research CouncilNatureParasitesPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenotypePopulationPopulation StudyPositioning AttributePredispositionPreparationPreventiveProductionProgressive DiseaseReactionRelative (related person)ResearchResearch ActivityResearch InfrastructureResearch PersonnelResearch ProposalsResistanceRoleSTAT6 geneSeminalSmall Interfering RNASoldierStagingStudentsSudanTestingTherapeutic InterventionTrainingTravelUnited States National Institutes of HealthUniversitiesUp-RegulationVector-transmitted infectious diseaseVisceralVisceral LeishmaniasisVisitWorkWritingacquired immunityarginasechemotherapycohortcytokinedesignhealinghuman diseaseimpaired capacityin vitro Modelin vivointerestkillingsmacrophagemeetingsmembermonocyteparent grantpermissivenesspre-clinicalprofessorprogramspublic health relevanceresistance mechanismresponseuniversity student
项目摘要
DESCRIPTION (provided by applicant): The proposed collaboration between the U.S. investigator (Dr. Peter Melby, UTHSCSA, San Antonio) and the foreign investigator (Dr. Sara Robledo, University of Antioquia, Medellin, Colombia) is an extension of NIH grant R01AI61624, on which Dr. Melby is the PI. Experimental animal studies have identified a dominant role for alternatively activated macrophages (AAMs) in the pathogenesis of cutaneous and visceral leishmaniasis, but their role in human susceptibility and disease has not been determined. The proposed FIRCA grant will extend the experimental animal studies to humans by investigating a previously studied population of individuals who were either classified as resistant (no clinical infection but positive DTH reaction to Leishmania antigen) or susceptible (chronic non-healing cutaneous leishmaniasis). Previous in vitro studies determined that macrophages from susceptible individuals had reduced capacity to control Leishmania infection compared to macrophages from resistant individuals, but the mechanism of this susceptibility is unknown. The overall hypothesis of this proposal is that nonhealing or progressive leishmaniasis is mediated through alternative macrophage activation, which impairs parasite killing. For all of the proposed studies, an in vitro model of Leishmania- infected monocyte-derived macrophages (MDMs), isolated from resistant or susceptible individuals, will be used. The first Specific Aim will test the hypothesis that macrophages from susceptible individuals respond directly to Leishmania infection through a program of alternative activation. The MDMs will be infected with L. (V.) panamensis (dermatropic strain) or L. (L.) donovani (viscerotropic strain), and markers of classical (NO production, NOS2 expression, and CCL3 production) and alternative macrophage activation (arginase activity, IL-10, CCL17, and CCL22 production, and expression of CD23) will be used to determine if Leishmania infection directly induces alternative activation, and if it is associated with susceptibility. The second Specific Aim will test the hypothesis that macrophages from susceptible individuals, when infected with Leishmania, become more sensitive to alternative activation effect of type 2 cytokines. Exposure of uninfected and Leishmania-infected MDMs to IL-4, IL-10, or IL-13 will determine if there is an additive or synergistic effect of the parasites and cytokines in the activation of STAT6 and upregulation of AAM genes. The third Specific Aim will use siRNA- mediated knockdown of STAT6 to test the hypothesis that the program of alternative macrophage activation is STAT6-dependent, and that inhibition of STAT6 activation in susceptible human macrophages will enhance their IFN-3-induced anti-leishmanial response. PUBLIC HEALTH RELEVANCE: Leishmaniasis is a vector borne disease that is endemic throughout much of the world, for which control strategies have largely been unsuccessful or non-sustainable. Cutaneous leishmaniasis is an emerging and re-emerging disease in many parts of the world, and in Colombia the number of cases of cutaneous leishmaniasis has increased dramatically in the past 4 years. Recent epidemics of visceral leishmaniasis have resulted in several hundred thousand deaths in India and Sudan. The poor response to chemotherapy and paucity of available drugs make investigation into the mechanisms of disease, and the identification of preventive or therapeutic interventions, of paramount importance.
描述(由申请人提供):美国调查员(彼得·梅尔比博士,UTHSCSA,圣安东尼奥)和外国研究员(哥伦比亚梅德林安提奥基亚大学的萨拉·罗布莱多博士)之间的拟议合作是NIH授予R01AI61624的延伸。实验动物研究已经确定了在皮肤和内脏利什曼病的发病机理中替代激活的巨噬细胞(AAM)的主要作用,但是尚未确定它们在人类敏感性和疾病中的作用。拟议的FIRCA赠款将通过研究先前研究的个体人群将实验性动物研究扩展到人类,这些个体被归类为抗药性(无临床感染,而是对利什曼原虫抗原的阳性反应)或易感性(慢性非控制皮肤利什曼病)。先前的体外研究确定,与抗性个体的巨噬细胞相比,易感人群的巨噬细胞控制着控制利什曼原虫感染的能力,但这种敏感性的机制尚不清楚。该提案的总体假设是,通过替代性巨噬细胞激活介导了非处理或进行性利什曼病,这会损害寄生虫的杀戮。对于所有提出的研究,将使用从耐药或易感个体中分离出的利什曼原虫感染单核细胞衍生的巨噬细胞(MDMS)的体外模型。第一个具体目的将检验以下假设:易感人物的巨噬细胞通过替代激活程序直接反应利什曼原虫感染。 MDM将被L.(V。)Panamensis(皮肤菌株)或L.(L。)Donovani(内脏菌株)以及古典(无生产,NOS2表达和CCL3产生)和替代性巨噬细胞激活(IL-10,IL-10,CCL17,CCL17,CCL17,以及CCL12的生产),以及CCL12的生产,以及CCL12的生产,并确定CCL17,以及CCL12的生产,并确定CCL12的生产,并确定CCL12的生产,并确定CCL12的生产,并确定CCL12的生产,并确定CCL12的生产,并确定CCL12的生产,并确定CCL12的生产以及利什曼原虫感染直接诱导替代激活,如果它与易感性相关。第二个特定目的将检验以下假设:易感个体的巨噬细胞在感染利什曼原虫时对2型细胞因子的替代激活效应更加敏感。未感染和利什曼尼亚感染的MDM暴露于IL-4,IL-10或IL-13将确定寄生虫和细胞因子在激活STAT6和AAM基因上调中是否存在添加剂或协同作用。第三个具体目的将使用SIRNA介导的STAT6敲低来检验以下假设:替代巨噬细胞激活程序是Stat6依赖性的,并且在易感人类巨噬细胞中抑制Stat6激活将增强其IFN-3诱导的抗脊髓抗反应。公共卫生相关性:利什曼病是一种媒介传播的疾病,在世界上大部分地区都是地方性的,因为控制策略在很大程度上是不成功或不可持续的。皮肤利什曼病是世界许多地方的一种新兴和重新出现的疾病,在哥伦比亚,皮肤利什曼病的病例数量在过去4年中急剧增加。内脏利什曼病的最近流行病导致印度和苏丹死亡数十万人。对化学疗法和可用药物的缺乏的反应不佳,可以调查疾病机制,以及对预防或治疗干预措施的鉴定,至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Peter C. Melby其他文献
<em>In situ</em> cytokines (IL-4, IL-10, IL-12, IFN-γ) and chemokines (MCP-1, MIP-1α) gene expression in human <em>Leishmania</em> (<em>Leishmania</em>) <em>mexicana</em> infection
- DOI:
10.1016/j.cyto.2014.05.016 - 发表时间:
2014-09-01 - 期刊:
- 影响因子:
- 作者:
Guillermo Valencia-Pacheco;Elsy Nalleli Loría-Cervera;Erika Ivett Sosa-Bibiano;Elsy B. Canché-Pool;Alberto Vargas-Gonzalez;Peter C. Melby;Fernando J. Andrade-Narvaez - 通讯作者:
Fernando J. Andrade-Narvaez
Concentration of Pentostam in human breast milk.
人母乳中 Pentostam 的浓度。
- DOI:
10.1016/0035-9203(89)90327-1 - 发表时间:
1989 - 期刊:
- 影响因子:2.2
- 作者:
Jonathan D. Berman;Peter C. Melby;Franklin A. Neva - 通讯作者:
Franklin A. Neva
Peter C. Melby的其他文献
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{{ truncateString('Peter C. Melby', 18)}}的其他基金
Physician-Scientist Training in Emerging Infectious Diseases
新发传染病的医师科学家培训
- 批准号:
10647762 - 财政年份:2021
- 资助金额:
$ 3.38万 - 项目类别:
Physician-Scientist Training in Emerging Infectious Diseases
新发传染病的医师科学家培训
- 批准号:
10270872 - 财政年份:2021
- 资助金额:
$ 3.38万 - 项目类别:
Mechanisms of Parasite Dissemination in Visceral Leishmaniasis
内脏利什曼病寄生虫传播机制
- 批准号:
10062846 - 财政年份:2017
- 资助金额:
$ 3.38万 - 项目类别:
Mechanisms of Parasite Dissemination in Visceral Leishmaniasis
内脏利什曼病寄生虫传播机制
- 批准号:
10302274 - 财政年份:2017
- 资助金额:
$ 3.38万 - 项目类别:
Malnutrition-related Lymph Node Dysfunction and Risk of Visceral Leishmaniasis
营养不良相关的淋巴结功能障碍和内脏利什曼病的风险
- 批准号:
8702843 - 财政年份:2014
- 资助金额:
$ 3.38万 - 项目类别:
Discovery of 4-aminoquinoline therapeutics for visceral leishmaniasis
发现内脏利什曼病的 4-氨基喹啉疗法
- 批准号:
8207443 - 财政年份:2010
- 资助金额:
$ 3.38万 - 项目类别:
NOS2 and arginase in visceral leishmaniasis-FIRCA supplement
内脏利什曼病中的 NOS2 和精氨酸酶 - FIRCA 补充剂
- 批准号:
7559198 - 财政年份:2009
- 资助金额:
$ 3.38万 - 项目类别:
NOS2 and arginase in visceral leishmaniasis-FIRCA supplement
内脏利什曼病中的 NOS2 和精氨酸酶 - FIRCA 补充剂
- 批准号:
8012292 - 财政年份:2009
- 资助金额:
$ 3.38万 - 项目类别:
NOS2 and arginase in visceral leishmaniasis
内脏利什曼病中的 NOS2 和精氨酸酶
- 批准号:
7347521 - 财政年份:2005
- 资助金额:
$ 3.38万 - 项目类别:
NOS2 and arginase in visceral leishmaniasis
内脏利什曼病中的 NOS2 和精氨酸酶
- 批准号:
7009285 - 财政年份:2005
- 资助金额:
$ 3.38万 - 项目类别:
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