T. cruzi: pathogenesis modulation by eicosanoids

T. cruzi：类二十烷酸的发病机制调节

• 批准号: 7793890
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 3.22万
• 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/7793890
• 关键词: Adherence; Adhesions; Affect; Biology; Blood Platelets; Blood Vessels; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell Proliferation; Cells; Chagas Disease; Cultured Cells; Disease; Eicosanoid Modulation; Eicosanoids; Endothelial Cells; Enzymes; Genes; Growth; Health; Heart Diseases; Human; In Vitro; Infection; Inflammatory; Knock-out; Knockout Mice; Laboratories; Leukocytes; Mediating; Modeling; Mus; 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; Research; Role; Second Messenger Systems; Signal Pathway; Smooth Muscle Myocytes; Stream; Therapeutic Intervention; Thromboxane Receptor; Thromboxanes; Thrombus; Tissues; Trypanosoma cruzi; Vascular Permeabilities; Vasospasm; Wild Type Mouse; 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

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.

类二十烷酸是健康和疾病中心血管系统的重要介质。 心肌炎是心血管疾病的重要病因之一， 世界上许多地方性疾病流行的地区。感染寄生虫T.克鲁兹引起了这种疾病， 具有许多类似于某些类二十烷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。它也会引起血管收缩， 血小板聚集和平滑肌细胞增殖。我们的初步数据显示， 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 关系在分离自TP敲除（KO）和WT小鼠的内皮细胞（EC）中 我们发现突变的TP在TP-KO EC中的表达可以用作解剖 细胞内寄生虫生长的分子调控。我们证明了G-alpha q或Galpha11 部分负责控制细胞内寄生虫的生长。我们将执行 进一步的实验，以确认这些途径是直接负责 通过宿主TP抑制寄生虫生长，从而定义了 第二信使影响寄生虫的生长。待检查的终点包括 这些细胞对这种寄生虫的易感性，粘附和渗透，寄生虫生长和 G α-q的下游信号通路。从各种常规和 KO小鼠将用于确定该感染发病机制中的重要途径。 除了EC以外的细胞也有TP，但在我们的研究中，我们使用小鼠心脏EC，因为它们是 容易获得、易于转染并保持其表型。其他细胞类型，如 小鼠心肌细胞难以获得纯的形式，并且不能保持其表型 在文化中。因此，EC充当所有具有TP的细胞的替代物，并且是TP的模型。 表征TP信号传导的影响。在小鼠中，类花生酸的各个部分 已删除的信号通路将用于评估在细胞内重要的信号通路。 冠心病的发病机制。鉴定并克隆了一种假定的血栓素 我们还计划检测类花生酸科斯和类花生酸合酶基因， 这些科斯的表型。类二十烷酸途径已经提供了靶点， 心血管疾病的治疗，我们目前的研究可能会提供额外的 治疗这种重要的人类寄生虫病的目标。