INVESTIGATION OF EARLY LEAD ANTI-TOXOPLASMA COMPOUNDS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 弓形虫是一种人畜共患寄生虫，广泛分布于世界各地。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)和流产有关外，弓形虫病还困扰着越来越多的免疫功能受损的人(癌症和移植患者)。原发感染(通过摄入含有CONTAM的水、土壤或熟肉中的包囊获得)导致速殖子寄生虫的最初全身传播，症状轻微或没有症状，感染后一周成熟为缓体组织包囊。与强烈影响胎儿的原发母体感染不同，免疫抑制患者群体中的疾病主要是由于患者组织中休眠的缓体包囊重新激活，可能导致显著的发病率。大约30%的美国人口长期感染弓形虫，并在他们的组织中，特别是大脑和肌肉中含有对化学和免疫具有抗药性的缓殖子包囊。已发表的研究表明，终生感染可能会在人类中产生心理表型；然而，目前还没有已知的治疗慢性缓体阶段感染的方法。最近，我们发表了一项关于非专利化合物抑制弓形虫细胞内速殖子生长的研究；然而，我们还没有建立它们的作用机制。此外，这些化合物对缓殖子包囊的影响仍未得到测试。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。我们将调查以下具体目标： 具体目的1：预测早期铅抗弓形虫化合物的可能作用机制。 具体目的2：评价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.