Regulation of Pulmonary Host Defense by Leptin
瘦素对肺宿主防御的调节
基本信息
- 批准号:7332253
- 负责人:
- 金额:$ 35.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-01-01 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcquired Immunodeficiency SyndromeAdipose tissueAlveolarAlveolar MacrophagesAnimalsAnti-Bacterial AgentsBacteriaBacterial InfectionsBacterial PneumoniaCellsCessation of lifeChronic DiseaseCommunitiesDefectDevelopmentEnd PointEnergy IntakeExhibitsFastingGoalsHormonesHost DefenseImmune responseImmunityImpairmentIn VitroIndividualInfectionKineticsLeptinLeptin deficiencyLeukotrienesLungMalignant NeoplasmsMalnutritionMusMutant Strains MiceNatural ImmunityNeutrophil InfiltrationPhagocytosisPneumococcal PneumoniaPneumoniaProductionPulmonary EmphysemaReceptor SignalingRegulationRoleSignal PathwaySourceStreptococcus pneumoniaeTestingTherapeutic AgentsTimeTransgenic MiceUpper respiratory tractWild Type Mousecytokinein vivoinsightkillingsleptin receptormacrophagemortalityneutrophilnovelpathogenperipheral bloodreconstitutionresponse
项目摘要
DESCRIPTION (provided by applicant): Streptococcus pneumoniae is the most common cause of community-acquired pneumonia accounting for 40,000 deaths/year in the US. Individuals who are most susceptible to pneumococcal pneumonia include those who are energy malnourished as a secondary consequence of chronic diseases such as cancer, emphysema, and AIDS. The mechanisms responsible for impaired innate immunity against bacterial infections arising from energy malnutrition are poorly understood. Leptin is hormone produced by adipose tissue that is reduced in the energy malnourished and is known to regulate innate immune responses. We have observed that leptin-deficient mice are more susceptible to bacterial pneumonia and alveolar macrophages (AMs) and neutrophils (PMNs) obtained from these animals exhibit defects in phagocytosis and killing of bacteria in vitro. The exogenous administration of leptin in vivo and in vitro to leptin-deficient animals reconstitutes antibacterial host defense endpoints in vivo and in vitro. We hypothesize that leptin regulates alveolar macrophage effector functions, neutrophil recruitment, and cytokine and leukotriene synthesis in the innate immune response against Streptococcus pneumoniae in vivo and in vitro. To test this hypothesis we will explore the following aims: 1) Assess the role of endogenous leptin in survival, bacterial clearance, and cellular recruitment following S. pneumoniae challenge by blocking leptin receptor signaling in vivo using a pharmacologic antagonist and leptin receptor transgenic mice; 2) Determine the kinetics and cellular sources of leptin production during the course of pneumococcal pneumonia and the target cells in the lung for its action; 3) Examine the importance of distinct leptin receptor signaling pathways in AM and PMN phagocytosis and killing of S. pneumoniae in vitro using cells from leptin receptor signaling mutant mice; and 4) Determine the effects of leptin administered at different time points following S. pneumoniae administration on bacterial clearance, survival, and AM and PMN mechanisms of phagocytosis and killing in normal mice. These studies will, for the first time, define leptin production and responses in the context of bacterial pneumonia and provide novel insights into the mechanisms by which leptin regulates innate immune responses against bacterial pathogens. They will also test the use of exogenous leptin as an adjunctive therapeutic agent in the treatment of pneumococcal pneumonia.
描述(由申请人提供):肺炎链球菌是社区获得性肺炎的最常见原因,在美国,每年40,000例死亡。 最容易受到肺炎球菌肺炎的个体包括那些能量营养不良的人,因为癌症,肺气肿和艾滋病等慢性疾病的次要后果。 对能量营养不良引起的细菌感染的造成的造成的先天免疫力受损的机制知之甚少。 瘦素是由脂肪组织产生的激素,在营养不良的能量中降低,已知可以调节先天免疫反应。 我们已经观察到,缺乏瘦素的小鼠更容易受到细菌性肺炎和肺泡巨噬细胞(AMS)和嗜中性粒细胞(PMN)(PMN)的影响,从这些动物中获得的嗜中性粒细胞(PMN)表现出吞噬作用缺陷,并在体外杀死细菌。 瘦素在体内和体外对瘦素缺陷动物的外源给药,在体内和体外重构抗菌宿主防御终点。 我们假设瘦素可以调节肺泡巨噬细胞的功能,中性粒细胞的募集以及细胞因子和白细胞合成,这在对肺炎链球菌的先天免疫反应中,体内和体外。 为了检验这一假设,我们将探讨以下目的:1)通过使用药理拮抗剂和瘦素受体受体转基因小鼠在体内阻止瘦素受体信号传导,评估内源性瘦素在生存,细菌清除率和细胞募集中的作用; 2)确定肺炎球菌肺炎和肺中靶细胞的动力学生成的动力学和细胞来源,以进行作用; 3)检查在AM和PMN吞噬作用中不同的瘦素受体信号通路的重要性,并使用瘦素受体信号突变小鼠的细胞在体外杀死肺炎链球菌; 4)确定肺炎链球菌给药后在不同时间点施用的瘦素对吞噬作用的细菌清除,生存以及AM和PMN机制的影响,并在正常小鼠中杀死。 这些研究将首次在细菌性肺炎的背景下定义瘦素的产生和反应,并为瘦素调节对细菌病原体的先天免疫反应的机制提供新的见解。 他们还将测试外源瘦素作为肺炎球菌肺炎治疗的辅助治疗剂。
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 MANCUSO其他文献
PETER MANCUSO的其他文献
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{{ truncateString('PETER MANCUSO', 18)}}的其他基金
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