Developmental switches regulating tissue cyst formation

调节组织囊肿形成的发育开关

基本信息

批准号：
9980272
负责人：
Michael W White
金额：
$ 54.63万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
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/9980272
关键词：
Acute 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 Recurrent disease Reverse Transcription Risk Role Stress Tertiary Protein Structure Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Transcription Coactivator Transcription Repressor Treatment Failure asexual brain tissue chronic infection combat experimental study loss of function neglect novel strategies pathogen prevent recruit side effect therapy development transcription factor transmission process

项目摘要

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.

项目摘要对于数百万与此联系的人来说，弓形虫感染仍然是公共卫生每年病原体。在美国，超过5000万人被长期感染了弓形虫弓形虫由于这种感染可能导致永久性视力丧失。疾病控制和预防中心认为毒品是最五个最大的重要的被忽视的寄生虫感染。可以合理地对待个体（尽管副作用很大）但是，如果提出了临床弓形虫病，则缺乏治疗或预防组织囊肿的药物负责长期感染。这种疗法失败使受感染的高危个人一生中容易受到疾病复发的影响。了解发展机制需要负责组织囊肿形成，以开发疗法来打击终身疾病。这基于慢性疾病的弓形虫生物学是无性复制的可逆转化 tachyzoite进入潜在的Bradyzoite阶段。这种关键的发展过渡伴随着重要的基因表达的变化由定义不明的转录机制控制。最近的实验我们的小组已经确定了关键细胞周期调节和应力诱导的毒素APIAP2因子，以防止或激活铁二核基因表达。我们假设这些发现揭示了转录网络这可以指导速氮岩增长的竞争需求，而不是需要休眠组织囊肿的发展用于寄生虫传播。为了了解该转录网络的运行方式，我们提出了两个特定的特定目的：在AIM 1中，实验重点将是APIAP2转录阻遏物， tachyzoite细胞周期的后半部分，我们将在分子水平上定义其机制，并且在细胞培养和寄生虫发育的动物模型中表征。在AIM 2中，我们将确定压力诱导的APIAP2阻遏物和激活剂竞争以控制胸肌基因表达和确定这些机制如何影响中间宿主中的弓形虫发育。