T. cruzi: pathogenesis modulation by eicosanoids

T. cruzi：类二十烷酸的发病机制调节

• 批准号: 7727927
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 46.19万
• 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/7727927
• 关键词: Adhesions; Affect; Arachidonic Acids; Area; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cells; Chagas Disease; Characteristics; Data; Disease; Eicosanoid Modulation; Eicosanoids; Endothelial Cells; G(q) Alpha; Genes; Growth; Health; Heart Diseases; Host-Parasite Relations; Human; Infection; Inflammatory; Knock-out; Knockout Mice; Mediator of activation protein; Modeling; Molecular; Mus; Mutate; Names; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Penetration; Phenotype; Platelet aggregation; Predisposition; Principal Investigator; Prostaglandins; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stream; Thromboxanes; Trypanosoma cruzi; cell type; programs; receptor; research study; 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。查加斯心肌病是世界许多流行地区心血管疾病的最重要原因之一。感染克氏锥虫会引起这种疾病，其许多特征与某些类二十烷酸（如血栓素）的作用相似。这种感染导致炎症级联的激活。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 TP-KO EC 中突变 TP 的表达可用作剖析细胞内寄生虫生长的分子调节的方法。我们证明 G-alpha q 或 G-alpha11 在一定程度上负责控制细胞内寄生虫的生长。我们将进行额外的实验来确认这些途径直接负责宿主 TP 抑制寄生虫生长，从而确定第二信使影响寄生虫生长的机制。要检查的终点包括这些细胞对这种寄生虫的敏感性、粘附和渗透、寄生虫生长和 G α -q 的下游信号传导途径。从各种常规小鼠和 KO 小鼠中获得的 EC 将用于确定这种感染发病机制的重要途径。 EC 以外的细胞都具有 TP，但在我们的研究中，我们使用小鼠心脏 EC，因为它们易于获得、易于转染并保持其表型。其他细胞类型，例如小鼠心肌细胞，很难以纯形式获得，并且在培养物中不能保持其表型。因此，EC 可作为所有 TP 细胞的替代品，并且是表征 TP 信号传导效应的模型。类二十烷酸途径各部分已被删除的小鼠将用于评估恰加斯心脏病发病机制中重要的信号传导途径。在从这种寄生虫中鉴定并克隆了假定的血栓素合酶基因后，我们还计划检查类二十烷酸 KO 并表征这些 KO 的表型。类二十烷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这种重要的人类寄生虫病的治疗提供额外的靶点。由花生四烯酸合成的类二十烷酸是心血管系统中的重要介质。我们的研究表明，类二十烷酸是由寄生虫克氏锥虫合成的，它是与心血管异常相关的南美锥虫病的病原体。我们计划研究类二十烷酸及其受体在心脏病的这一重要原因中的作用。