T. cruzi: pathogenesis modulation by eicosanoids

二十烷基类化合物是心血管系统在健康和疾病中的重要介体。 查吉斯心肌病是中国心血管疾病最重要的原因之一。 世界上许多地方病流行地区。感染寄生虫克氏锥虫会导致这种疾病 具有许多类似于某些二十烷类化合物的作用的特征，如血栓烷。 这种感染会导致炎症级联反应的激活。它还会引起血管收缩， 血小板聚集和血管平滑肌细胞增殖。我们的初步数据显示 来自宿主血栓素类前列腺素受体(TP)的离散信号通路调节寄主寄生虫 两性关系。从TP基因敲除(KO)和WT小鼠分离的内皮细胞(ECs) 我们发现突变的TP在TP-KO内皮细胞中的表达可以作为一种解剖方法 细胞内寄生虫生长的分子调控。我们证明了G-Alpha Q或Galpha11 在一定程度上负责控制细胞内寄生虫的生长。我们将表演 更多的实验证实这些通路直接导致了 寄主茶多酚抑制寄生虫生长，从而确定其机制(S) 第二信使影响寄生虫的生长。要检查的端点包括 这些细胞对这种寄生虫的敏感性、黏附和穿透、寄生虫的生长和 Gα-Q的下游信号通路。ECS是从各种常规和 KO小鼠将被用来确定这种感染的发病机制中的重要途径。 除内皮细胞外，其他细胞都有TP，但在我们的研究中，我们使用小鼠心脏内皮细胞，因为它们是 容易获得，易于转化，并保持其表型。其他单元类型，例如 小鼠心肌细胞，很难以纯形式获得，并且不能保持其表型 在文化上。因此，内皮细胞充当所有患有TP的细胞的替代品，并且是 TP信号影响的特征。小鼠体内不同部位的二十烷类化合物 途径已被删除将被用来评估信号通路在 心脏失调症的发病机制。鉴定并克隆了一种可能的血栓烷 我们还计划检测二十烷类KO并鉴定这种寄生虫的合成酶基因 这些KO的表型。二十烷类化合物途径已经为 心血管疾病的治疗和我们目前的研究可能会提供额外的 这一重要的人类寄生虫病的治疗目标。

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 vasocontriction, platelet aggregation and and smooth muscle cell proliferation. Our preliminary data indicate that discrete signaling pathways from host thromboxane prostanoid recptor (TP) regulate the hostparasite 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 Galpha11 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 messengers 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 chatacterize 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.