INVESTIGATION OF EARLY LEAD ANTI-TOXOPLASMA COMPOUNDS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 弓形虫是一种分布于世界各地的人畜共患寄生虫。 除了与胎儿畸形（先天性神经病的主要原因，在美国影响1/1000的活产婴儿）和流产的经典关联外，弓形虫病还困扰着越来越多的免疫功能低下的个体（癌症和移植患者）。 原发性感染（通过摄入污染的水、土壤或未煮熟的肉中的包囊获得）导致速殖子寄生虫的初始全身传播，症状轻微至无症状，感染后1周成熟为缓殖子组织包囊。 与强烈影响胎儿的原发性母体感染相反，免疫抑制患者群体中的疾病主要是由于驻留在患者组织中的休眠的缓殖子包囊的重新激活，并且可以导致显著的发病率。 大约30%的美国人口是T.弓形虫，并且在它们的组织，特别是脑和肌肉内具有化学和免疫抗性的缓殖子包囊。 已发表的研究表明，终身感染可能会在人类中产生心理表型;然而，对于慢性缓殖子感染阶段没有已知的治疗方法。 最近，我们发表了一项关于非专利化合物对细胞内弓形虫速殖子生长有活性的研究;然而，我们还没有确定其作用机制。 此外，这些化合物对缓殖子包囊的影响尚未得到证实。 因此，我们建议研究这些早期铅抗弓形虫化合物的作用机制，并研究这些化合物对缓殖子包囊的影响。 我们将研究以下具体目标： 具体目标1：预测早期铅抗弓形虫化合物的可能作用机制。 具体目标2：评估早期先导化合物对弓形虫缓殖子的杀灭效果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toxoplasma gondii is a zoonotic human parasite with worldwide distribution. In addition to its classical association with fetal malformation (a leading cause of congenital neuropathy, affecting 1/1000 live births in the US) and abortion, toxoplasmosis also afflicts the growing ranks of immunocompromised individuals (cancer and transplant patients). Primary infection (acquired via ingestion of cysts in contam¿inated water, soil, or under¿cooked meat) leads to an initial systemic spread of tachyzoite parasites with mild to no symptoms, which mature into bradyzoite tissue cysts 1 week post-infection. In contrast to primary maternal infection which strongly affects the fetus, disease in the immunosuppressed patient population is primarily due to reactivation of dormant bradyzoite cysts residing in patient tissues and can lead to significant morbidity. Approximately 30% of the U.S. population is chronically infected with T. gondii, and harbor chemo- and immuno-resistant bradyzoite cysts within their tissues, particularly brain and muscle. Published studies have suggested that lifelong infection may produce psychological phenotypes in humans; however, there is no known treatment for the chronic bradyzoite stage of infection. Very recently, we have published a study of non-proprietary compounds active against intracellular Toxoplasma gondii tachyzoite growth; however, we have not established their mechanism of action. Moreover, the effect of these compounds on the bradyzoite cysts remains untested. Therefore, we propose to investigate the mechanism of action for these early lead anti-Toxoplasma compounds, and investigate the effect these compounds exert on bradyzoite cysts. We will investigator the following specific aims: Specific Aim 1: Predict the likely mechanism of action of early lead anti-Toxoplasma compounds. Specific Aim 2: Assess the killing efficacy of early lead compounds against Toxoplasma gondii bradyzoites.