Developmental switches regulating tissue cyst formation

项目摘要 弓形虫感染仍然是一个公共卫生危害数百万人接触这个 病原体每年在美国有超过5000万人慢性感染弓形虫 成千上万的健康人由于这种感染而患上眼病， 视力丧失疾病控制和预防中心认为弓形虫是五种最常见的疾病之一。 被忽视的寄生虫感染个体可以合理治疗（尽管有显著的副作用） 然而，如果出现临床弓形虫病，则缺乏治疗或预防组织囊肿的药物， 导致长期感染。这种治疗失败会使处于感染风险中的个体 在他们的一生中很容易复发。了解发展机制 需要开发治疗方法来对抗终身疾病。的 弓形虫生物学是慢性疾病的基础，是无性复制的可逆转化。 速殖子进入潜伏的缓殖子阶段。这一关键的发展转型伴随着重大的 基因表达的变化由不明确的转录机制控制。最近的实验 我们的小组已经确定了关键的细胞周期调节和应激诱导的弓形虫ApiAP2因子， 或激活缓殖子基因表达。我们假设这些发现揭示了一个转录网络 它指导速殖子生长的竞争需求， 寄生虫传播的可能性为了理解这个转录网络是如何运作的，我们提出了两个具体的 目的：在目的1中，实验重点将是ApiAP 2转录抑制因子，其在细胞中表达。 速殖子细胞周期的后半部分，我们将在分子水平上定义其机制， 在细胞培养和寄生虫发育的动物模型中进行表征。在目标2中，我们将确定 应激诱导ApiAP 2阻遏物和激活物竞争控制缓殖子基因表达， 确定这些机制如何影响中间宿主中弓形虫的发育。

Project Summary Toxoplasma gondii infections continue to be a public health hazard for millions of individuals that contact this pathogen annually. More than 50 million individuals in the US are chronically infected with Toxoplasma gondii and thousands of healthy individuals develop eye disease due to this infection that can lead to permanent vision loss. The Centers for Disease Control and Prevention considers Toxoplasma one of the five most important neglected parasitic infections. Individuals can be reasonably treated (despite significant side effects) if clinical toxoplasmosis is presented, however, there is a lack of drugs to treat or prevent the tissue cyst that is responsible for long-term infections. This therapy failure leaves at-risk individuals who become infected vulnerable to disease relapse throughout their lifetimes. Understanding the developmental mechanisms responsible for tissue cyst formation are needed to develop therapies to combat life-long disease. The Toxoplasma biology that underlies chronic disease is a reversible transformation of the asexual replicating tachyzoite into the latent bradyzoite stage. This critical developmental transition is accompanied by significant changes in gene expression controlled by poorly defined transcriptional mechanisms. Recent experiments of our group have identified key cell cycle regulated and stress-induced Toxoplasma ApiAP2 factors that prevent or activate bradyzoite gene expression. We hypothesize these discoveries reveal a transcriptional network that directs the competing needs of tachyzoite growth against development of the dormant tissue cyst required for parasite transmission. To understand how this transcriptional network operates, we propose two specific aims: In Aim 1, the experimental focus will be ApiAP2 transcriptional repressors that are expressed in the second half of the tachyzoite cell cycle whose mechanisms we will define at the molecular level and characterize in cell culture and animal models of parasite development. In Aim 2, we will determine how the stress-induced ApiAP2 repressors and activators compete to control bradyzoite gene expression and determine how these mechanisms influence Toxoplasma development in the intermediate host.