Developmental switches regulating tissue cyst formation

调节组织囊肿形成的发育开关

• 批准号: 9383727
• 负责人: Michael W White
• 金额: $ 57.07万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383727
• 关键词: Acute; Adverse effects; Affect; Age; Animal Model; Animals; Antigens; Biochemical; Biology; Blindness; Cell Culture Techniques; Cell Cycle; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Disease; Clinical; Complex; Cyst; DNA Binding Domain; DNA Sequence; Development; Disease; Drug or chemical Tissue Distribution; Environment; Equilibrium; Eye diseases; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Growth; Health Hazards; Immune response; Immune system; Individual; Infection; Investments; Knock-out; Lead; Learning; Life; Life Cycle Stages; Modeling; Molecular; Mus; Nuclear Protein; Outcome; Parasites; Parasitic infection; Pharmaceutical Preparations; Population; Proteins; Public Health; Recruitment Activity; Recurrent disease; Reverse Transcription; Risk; Role; Stress; Tertiary Protein Structure; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transcription Coactivator; Transcription Repressor/Corepressor; Treatment Failure; asexual; brain tissue; combat; disorder prevention; experimental study; loss of function; neglect; novel strategies; pathogen; prevent; therapy development; transcription factor; transmission process

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.

项目摘要 弓形虫感染仍然是数百万接触过弓形虫的人的公共健康威胁。 每年都有病原体。美国超过5000万人慢性感染弓形虫 数以千计的健康人由于这种感染而患上眼病，这种感染可能导致永久性的 视力丧失。疾病控制和预防中心认为弓形虫是五大 重要的被忽视的寄生虫感染。个人可以得到合理的治疗(尽管有明显的副作用) 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 对长期感染负责。这种治疗失败使感染的高危个体 易患疾病的人一生中都会复发。理解发育机制 负责组织囊肿形成的人需要开发与终身疾病作斗争的治疗方法。这个 弓形虫生物学是慢性疾病的基础，是无性复制的可逆转变 速殖子进入潜伏缓殖子阶段。这一关键的发展转型伴随着显著的 基因表达的变化由不明确的转录机制控制。最近的实验 我们的团队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，这些因子可以防止 或激活缓殖子基因的表达。我们假设这些发现揭示了转录网络 这使速殖子生长的竞争需求与所需的休眠组织囊的发展相对应。 用于寄生虫传播。为了了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：在目标1中，实验的重点将是ApiAP2转录抑制物，这些转录抑制物在 速殖子细胞周期的后半部分，我们将在分子水平和 在细胞培养和寄生虫发育的动物模型中具有特点。在目标2中，我们将确定 应激诱导的ApiAP2抑制子和激活子竞争控制缓殖子基因的表达和 确定这些机制如何影响中间宿主中的弓形虫发育。