Targeting Entry Pathways in Leishmaniasis
瞄准利什曼病的进入途径
基本信息
- 批准号:8588893
- 负责人:
- 金额:$ 4.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-12-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdhesionsAdverse effectsAffectAntimonyAntiparasitic AgentsAwardBindingBiochemicalBiochemistryBiological AssayC3biCellsCellular biologyChildhoodClinicalClinical TrialsCommunicable DiseasesComplementComplement ReceptorCutaneousCutaneous LeishmaniasisDataDefectDiseaseDoctor of PhilosophyEnergy TransferFamilyFc ReceptorFellowshipFibroblastsGenesGleevecGoalsImatinibImmune systemImmunoglobulin GImmunoglobulinsInfectionIntegrin BindingIntegrinsInterventionKnowledgeLaboratoriesLeadLeishmaniaLeishmaniasisLesionLifeLife Cycle StagesMacrophage-1 AntigenMediatingMembraneMentorsMicrobiologyMiltefosineMolecularMusParasitesParasitologyPathogenesisPathway interactionsPhagocytesPhagocytosisPharmaceutical PreparationsPharmacologyPhosphotransferasesProcessProtein Tyrosine KinaseProteinsReceptor SignalingRegulationResearchResearch PersonnelResistance developmentRoleSand FliesSeveritiesSideSignaling ProteinSkin UlcerStagingTestingTherapeuticToxoplasma gondiiTrainingVisceralWorkbasecancer therapycareerexperienceimprovedinhibitor/antagonistkillingskinase inhibitormacrophagemouse modelmutantnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionpolymerizationreceptorreceptor bindingsrc-Family Kinasestreatment strategyuptake
项目摘要
DESCRIPTION (provided by applicant): CANDIDATE/TRAINING: My goal for this career award is to obtain the necessary training to become an independent investigator in the molecular pathogenesis of Leishmania infection. I am a pediatric infectious diseases fellow who earned a Ph.D. in microbiology studying the parasite Toxoplasma gondii. During my fellowship, I began to study the mechanisms that regulate the uptake of Leishmania by macrophages. My Ph.D. provided me with experience in microbiology and cell biology, and I developed experience with mouse models of pathogenesis during my fellowship training. I now plan to develop additional expertise and mentored research experience in biochemistry and pharmacology, and relate it to the pathogenesis and treatment of leishmaniasis. My mentor is a biochemist who studies the mechanisms that regulate actin polymerization. I will also be mentored by a parasitologist with extensive experience in Leishmania infection and its regulation by the mouse immune system, a cell biologist who works on the mechanisms of integrin activation, and a pharmacologist. The combination of my previous research background, my clinical training, my research during my fellowship, and my mentored research and coursework during the K08 award period will enhance my scientific breadth of knowledge, and uniquely enable me to contribute to the field of molecular parasitology.
PROJECT: Leishmania is a parasite that causes cutaneous or visceral disease. Current therapies have significant side effects, and parasites are developing resistance to them, so new therapies are needed. Leishmania must live inside phagocytes to survive. Both life cycle stages, promastigotes and amastigotes, infect macrophages. Studying how Leishmania is engulfed by macrophages will help us understand its pathogenesis and could define new antiparasitic targets. My work shows that Abl family kinases permit uptake of Leishmania by macrophages, and that inhibiting these kinases ameliorates leishmaniasis in mice. This project further defines the mechanism by which Leishmania is engulfed by macrophages and causes disease, with the eventual goal that drugs that inhibit uptake will provide novel therapeutic strategies. I hypothesize 1) interactions between ¿2 integrin and Abl allow promastigote uptake by macrophages, 2) interactions among FcR, Src family kinases, and Arg allow amastigote uptake by macrophages, and 3) drugs that can inhibit these signaling proteins will decrease the manifestations of cutaneous leishmaniasis in mice. In Specific Aim 1, I will characterize the ¿2 integrin:Abl interaction and its role during promastigote uptake by macrophages. In Specific Aim 2, I will determine how Src family kinases affect amastigote uptake by macrophages and the severity of cutaneous leishmaniasis in mice. In Specific Aim 3, I will assess whether inhibitors of
parasite uptake by macrophages, alone or in combination with miltefosine, decrease the severity of cutaneous leishmaniasis in mice. My studies will elucidate the initial steps of parasit uptake, improve our understanding of the pathogenesis of leishmaniasis, and provide novel approaches to treat this devastating infection.
描述(由适用提供):候选人/培训:我的职业生涯奖项是获得必要的培训,以成为利什曼尼亚感染分子发病机理的独立研究者。我是一名儿科传染病研究员,获得了博士学位。研究寄生虫弓形虫弓形虫的微生物学。在奖学金期间,我开始研究巨噬细胞来调节利什曼尼亚吸收的机制。我的博士学位为我提供了微生物和细胞生物学方面的经验,在研究金培训期间,我开发了具有发病机理的小鼠模型的经验。我现在计划开发更多的专业知识,并改善了生物化学和药理学方面的研究经验,并将其与利什曼病的发病机理和治疗联系起来。我的心理是一位生物化学家,他研究调节肌动蛋白聚合的机制。我还将由一名寄生虫学家介绍,在利什曼尼亚感染方面具有丰富的经验及其对小鼠免疫系统的调节,一名从事整合素激活机制的细胞生物学家以及一家制药公司。我以前的研究背景,临床培训,研究金期间的研究以及我在K08奖项期间的心理研究和课程的结合将增强我的科学知识广度,并独特地使我能够为分子寄生虫学领域做出贡献。
项目:利什曼原虫是引起皮肤病或内脏疾病的寄生虫。当前的疗法具有重大的副作用,并且寄生虫正在对其产生抗性,因此需要新的疗法。利什曼尼亚必须生活在吞噬细胞内才能生存。两个生命周期阶段,前养护物和杂物,都感染了巨噬细胞。研究利什曼原虫如何被巨噬细胞吞没将有助于我们理解其发病机理,并可以定义新的抗寄生虫靶标。我的工作表明,ABL家族激酶允许巨噬细胞吸收利什曼尼亚,并且抑制这些激酶可以改善小鼠利什曼病。该项目进一步定义了利什曼尼亚被巨噬细胞吞没的机制并引起疾病,最终的目标是抑制摄取的药物将提供新颖的治疗策略。 i假设1)€2整合蛋白和ABL之间的相互作用允许巨噬细胞的前瞻性吸收,2)FCR之间的相互作用,SRC家族激酶之间的相互作用,而ARG允许巨噬细胞的混合吸收和3)可以抑制这些信号蛋白的药物,将抑制这些信号蛋白的表现。在特定的目标1中,我将表征„ 2整合素:ABL相互作用及其在巨噬细胞吸收前观测中的作用。在特定的目标2中,我将确定SRC家族激酶如何影响巨噬细胞的杂物摄取和小鼠皮肤利什曼病的严重程度。在特定目标3中,我将评估是否
巨噬细胞的寄生虫吸收,单独或与米尔特福修结合减少小鼠皮肤利什曼病的严重程度。我的研究将阐明寄生吸收的初始步骤,提高我们对利什曼病发病机理的理解,并提供新的方法来治疗这种毁灭性的感染。
项目成果
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Dawn Marie Wetzel其他文献
Dawn Marie Wetzel的其他文献
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