Defining the cell and molecular basis of Toxoplasma recrudescence

定义弓形虫复发的细胞和分子基础

基本信息

批准号：
10180280
负责人：
Michael W White
金额：
$ 73.49万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180280
关键词：
Acute Amylopectin Astrocytes Auxins Back Biological Cells Chromatin Chronic Chronic Disease Clinical Competence Consumption Cyclins Cyst Cytoplasmic Granules Development Developmental Process Disease Environment Epigenetic Process Face Fibroblasts Frequencies Gene Expression Genes Genetic Genetic Models Glucose Glycogen Goals Growth Health Hepatocyte Human Immunocompromised Host In Vitro Individual Kinetics Life Life Cycle Stages Metabolic Metabolism Methods Mitochondria Modeling Molecular Morphology Mus Muscle Fibers Parasites Parents Pathway interactions Population Proteins Protocols documentation Recombinants Recrudescences Research Role Specificity Sporozoites Testing Therapeutic Time Tissue Expansion Tissue Model Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Transcription Process Transgenic Organisms Yeasts cell type chronic infection conditional knockout epigenome experimental study genetic approach human pathogen innovation metabolomics pathogen preservation prevent single cell sequencing transcriptome transcriptome sequencing

Acute Amylopectin Astrocytes Auxins Back Biological Cells Chromatin Chronic Chronic Disease Clinical Competence Consumption Cyclins Cyst Cytoplasmic Granules Development Developmental Process Disease Environment Epigenetic Process Face Fibroblasts Frequencies Gene Expression Genes Genetic Genetic Models Glucose Glycogen Goals Growth Health Hepatocyte Human Immunocompromised Host In Vitro Individual Kinetics Life Life Cycle Stages Metabolic Metabolism Methods Mitochondria Modeling Molecular Morphology Mus Muscle Fibers Parasites Parents Pathway interactions Population Proteins Protocols documentation Recombinants Recrudescences Research Role Specificity Sporozoites Testing Therapeutic Time Tissue Expansion Tissue Model Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Transcription Process Transgenic Organisms Yeasts cell type chronic infection conditional knockout epigenome experimental study genetic approach human pathogen innovation metabolomics pathogen preservation prevent single cell sequencing transcriptome transcriptome sequencing

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项目摘要

Project Summary Reactivation of toxoplasmosis is a significant health threat to people chronically infected with this parasite and is life-threatening to infected individuals that are or become immunocompromised. Millions of people face this threat as it is estimated one third of human populations are infected with this pathogen. Recrudescence of the Toxoplasma bradyzoite tissue cyst is the cause of toxoplasmosis reactivation, which can not be prevented as there is no current treatment that eliminates the dormant tissue cyst in chronically infected individuals. Approaches to find therapeutic solutions to treat and prevent chronic toxoplasmosis have suffered from limited accessibility to the relevant Toxoplasma stages and a lack of accurate in vitro developmental models. Our goal in this proposal is to breakthrough these impasses. We have developed a new innovative ex vivo model of bradyzoite recrudescence that we will utilize to define the host cell specificity (Aim 1a), whole-cell gene expression (Aim 1b) and metabolic changes (Aim 2) that unfold when a bradyzoite converts back to the tachyzoite and also in a newly discovered alternate pathway where bradyzoites directly replicate to reform the tissue cyst. This information is critically needed in order to understand how we might prevent toxoplasmosis reactivation. The loss of developmental competency in vitro that is exacerbated in current protocols producing transgenic strains is also a major impediment to understanding the molecular basis of tissue cyst reactivation. In this proposal, we will implement and optimize an innovative approach to generate developmentally competent transgenic strains (Aim 3a), and use this new protocol to define cyclin and other protein mechanisms (Aim 3b) that have critical roles in regulating bradyzoite recrudescence and tissue cyst re-formation

项目摘要弓形虫病的重新激活是对长期感染的人的重大健康威胁这种寄生虫对被感染或成为的感染者威胁生命免疫功能低下。数以百万计的人面临着这种威胁，因为它估计是人类的三分之一种群被这种病原体感染。弓形虫的重生组织囊肿是弓形虫病再活化的原因，由于没有当前的治疗方法可以消除长期感染个体中休眠组织囊肿的治疗方法。寻找治疗和预防慢性弓形虫病的治疗解决方案的方法遭受相关毒品阶段的可访问性有限，缺乏准确的体外发展模型。我们在此提案中的目标是突破这些障碍。我们已经开发了一种新的Bradyzoite复发的新创新离体模型，我们将利用它定义宿主细胞特异性（AIM 1A），全细胞基因表达（AIM 1B）和代谢更改（AIM 2）Bradyzoite将转换回tachyzoite并在新发现的替代途径，在该途径中直接复制以改革组织囊肿。这些信息是至关重要的，以了解我们如何阻止弓形虫病重新激活。体外的发展能力丧失，这种能力恶化在当前产生转基因菌株的方案中，也是理解的主要障碍组织囊肿再活化的分子基础。在此提案中，我们将实施和优化一种创新的方法来产生发育能力胜任的转基因菌株（AIM 3A），并且使用此新方案来定义具有关键的细胞周期蛋白和其他蛋白质机制（AIM 3B）在调节铁二岩的复发和组织囊肿重建方面的作用