T. cruzi: pathogenesis modulation by eicosanoids

T. cruzi：类二十烷酸的发病机制调节

基本信息

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
项目类别：
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

项目摘要

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。查加斯心肌病是导致心血管疾病的最重要原因之一世界许多流行地区。感染克氏锥虫会导致这种疾病具有许多与某些类二十烷酸（例如血栓素）的作用相似的特性。这种感染导致炎症级联的激活。它还会引起血管收缩，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。从 TP 敲除 (KO) 和 WT 小鼠中分离的内皮细胞 (EC) 我们发现TP-KO ECs中突变TP的表达可以用作解剖的方法细胞内寄生虫生长的分子调节。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。我们将表演额外的实验以确认这些途径直接负责宿主 TP 抑制寄生虫生长，从而确定其机制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、粘附和渗透、寄生虫的生长和 G α -q 的下游信号通路。从各种常规和 KO 小鼠将用于确定这种感染发病机制的重要途径。除 EC 之外的细胞也具有 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中。因此，EC 可以作为所有 TP 细胞的替代品，并且是 TP信号传导效应的表征。小鼠体内的类二十烷酸的各个部分已删除的通路将用于评估重要的信号通路恰加斯心脏病的发病机制。鉴定并克隆了假定的血栓素我们还计划检查类二十烷酸 KO 并鉴定该寄生虫的合酶基因这些 KO 的表型。类二十烷酸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治疗这种重要的人类寄生虫病的目标。