T. cruzi: pathogenesis modulation by eicosanoids

T. cruzi：类二十烷酸的发病机制调节

• 批准号: 7348106
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 41.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348106
• 关键词: Adherence; Adhesions; Affect; Arachidonic Acids; Area; Biology; Blood Platelets; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell Proliferation; Cells; Chagas Disease; Characteristics; Cultured Cells; Data; Dinoprost; Disease; Eicosanoid Modulation; Eicosanoids; End Point; Endothelial Cells; Enzymes; G(q) Alpha; Genes; Growth; Health; Heart Diseases; Host-Parasite Relations; Human; In Vitro; Infection; Inflammatory; Knock-out; Knockout Mice; Laboratories; Leukocytes; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutate; Myocardial; NADPH Dehydrogenase; Parasitemia; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Penetration; Peripheral; Phenotype; Plasma; Platelet Activation; Platelet aggregation; Predisposition; Production; Property; Prostaglandins; Receptor Activation; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stream; Therapeutic Intervention; Thromboxane Receptor; Thromboxanes; Thrombus; Tissues; Trypanosoma cruzi; Vascular Permeabilities; Vasospasm; Wild Type Mouse; cell type; cyclooxygenase 1; cyclooxygenase 2; cytokine; human disease; in vivo; insight; interest; knockout gene; migration; monocyte; mortality; mouse model; neointima formation; parasitism; receptor; research study; response; second messenger; vasoconstriction

DESCRIPTION (provided by applicant): Eicosanoids are important mediators of the cardiovascular system in health and disease. Chagasic cardiomyopathy is one of the most important causes of cardiovascular diseases in many endemic areas of the world. Infection with the parasite T. cruzi causes this disease which has many characteristics similar to the effects of certain eicosanoids such as thromboxane. This infection leads to activation of the inflammatory cascade. It also causes vasoconstriction, platelet aggregation and smooth muscle cell proliferation. Our preliminary data indicate that discrete signaling pathways from host thromboxane prostanoid recptor (TP) regulate the host- parasite relationship. In endothelial cells (ECs) isolated from TP knockout (KO) and WT mice we found that expression of mutated TP in TP-KO ECs can be used as an approach to dissect the molecular regulation of intracellular parasite growth. We demonstrated that G-alpha q or G- alpha11 are responsible, in part, for the control of intracellular parasite growth. We will perform additional experiments to confirm that those pathways are directly responsible for the suppression of parasite growth by host TP and thus define the mechanism(s) through which second messenger's affects parasite growth. The endpoints to be examined include susceptibility of these cells to this parasite, adhesion and penetration, parasite growth and down-stream signaling pathways of G alpha -q. ECs obtained from various conventional and KO mice will be used to determine important pathways in the pathogenesis of this infection. Cells other than ECs have TP but in our studies we use murine cardiac ECs because they are readily obtained, easily transfectable and maintain their phenotype. Other cell types, such as murine cardiac myocytes, are difficult to obtain in pure form and do not maintain their phenotype in culture. Therefore, ECs act as a surrogate for all cells with TP and are a model for the characterization of the effects of TP signaling. Mice in which various parts of the eicosanoid pathway have been deleted will be used to evaluate signaling pathways important in the pathogenesis of chagasic heart disease. Having identified and cloned a putative thromboxane synthase gene from this parasite we also plan to examine eicosanoid KOs and characterize the phenotype of these KOs. The eicosanoid pathway has already provided targets for the treatment of cardiovascular disease and our current studies are likely to provide additional targets for the treatment of this important human parasitic disease. Eicosanoids which are synthesized from arachidonic acid are important mediators in the cardiovascular system. Our studies indicate that eicosanoids are synthesized by the parasite Trypanosoma cruzi, the causative agent of Chagas' disease which is associated with cardiovascular abnormalities. We plan to investigate the role of eicosanoids and their receptors in this important cause of heart disease.

描述（由申请人提供）：类二十烷酸是健康和疾病中心血管系统的重要介质。在世界上许多流行地区，心肌病是心血管疾病的最重要原因之一。感染寄生虫T. Cruzi引起的这种疾病具有许多类似于某些类花生酸如血栓烷的作用的特征。这种感染导致炎症级联反应的激活。它还引起血管收缩、血小板聚集和平滑肌细胞增殖。我们的初步数据表明，来自宿主血栓素前列腺素受体（TP）的离散信号通路调节宿主-寄生虫关系。在从TP敲除（KO）和WT小鼠分离的内皮细胞（EC）中，我们发现突变的TP在TP-KO EC中的表达可用作剖析细胞内寄生虫生长的分子调控的方法。我们证明，G-α q或G-α 11是负责，在一定程度上，为细胞内寄生虫生长的控制。我们将进行额外的实验，以确认这些途径是直接负责抑制寄生虫生长的主机TP，从而定义的机制（S）通过第二信使的影响寄生虫的生长。待检查的终点包括这些细胞对该寄生虫的易感性、粘附和穿透、寄生虫生长和G α-q的下游信号传导途径。从各种常规和KO小鼠获得的EC将用于确定这种感染的发病机制中的重要途径。除了EC以外的细胞具有TP，但在我们的研究中，我们使用鼠心脏EC，因为它们容易获得，易于转染并保持其表型。其他细胞类型，如鼠心肌细胞，难以获得纯的形式，并且在培养中不能保持其表型。因此，EC作为所有具有TP的细胞的替代物，并且是表征TP信号传导的作用的模型。类二十烷酸途径的各个部分已被删除的小鼠将用于评估在冠心病发病机制中重要的信号传导途径。在鉴定并克隆了一个假定的血栓素合酶基因后，我们还计划研究类花生酸科斯并表征这些科斯的表型。类花生酸途径已经为心血管疾病的治疗提供了靶点，我们目前的研究可能为治疗这种重要的人类寄生虫病提供额外的靶点。由花生四烯酸合成的类二十烷酸是心血管系统的重要介质。我们的研究表明，类花生酸是由寄生虫克氏锥虫合成的，克氏锥虫是与心血管异常相关的恰加斯病的病原体。我们计划研究类花生酸及其受体在心脏病这一重要病因中的作用。