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The cell cycle of T. gondii bradyzoites within tissue cysts:in vivo development of an HIV-AIDS opportunistic parasite

组织包囊内弓形虫缓殖子的细胞周期：HIV-AIDS机会性寄生虫的体内发育

基本信息

批准号：
9207417
负责人：
ANTHONY P. SINAI
金额：
$ 18.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207417
关键词：
Acquired Immunodeficiency Syndrome Acute Address Animals Biochemical Biology Blood Bromodeoxyuridine Cell Culture Techniques Cell Cycle Cell Cycle Progression Cerebral Toxoplasmosis Chronic Chronic Phase Cyst Cytokinesis DNA biosynthesis Data Development Disease Drosophila genus Effectiveness Encephalitis Event Exhibits Exploratory/Developmental Grant Foundations Gene Expression Generations Growth HIV Human Immunosuppression Incidence Infection Knowledge Label Life Life Cycle Stages Maintenance Meat Mediating Metabolic Metabolism Methodology Methods Molecular Monitor Nucleotides Oocysts Opportunistic Infections Oral Parasites Parasitic infection Pathogenesis Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phase Phosphotransferases Physiology Population Positioning Attribute Prevalence Refractory Regulation Reporter Research Role Serological Signal Transduction Source Specificity Standardization System Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Work base drug development high reward high risk imaging software immunological status in vivo insight latent infection programs public health relevance therapy development uptake

项目摘要

DESCRIPTION (provided by applicant): Toxoplasmic encephalitis (TE) is one of the HIV-AIDS defining opportunistic infections that is associated with the reactivation of the chronic form of te infection, mediated by bradyzoites, within tissue cysts in the CNS. Despite the central role in the pathogenesis of HIV-AIDS associated toxoplasmosis, little is known about the biology of tissue cysts and the bradyzoite stage of the parasite they contain. Among the key limitations in studying the progression of the chronic phase and the mechanisms by which latency is established, maintained and lost during reactivation has been that rigorous insights into the physiology and development of bradyzoites in vivo has not been possible. Toward removing this major limitation we have initiated a comprehensive research program to understand bradyzoite biology by the development of approaches that directly address bradyzoite replication within tissue cysts in the in vivo context. These initial studies reveal that bradyzoites possess a previously unappreciated capacity for replication and metabolism that can be exploited in the development drugs to target what has been a traditionally refractory state. With the present study we aim to establish not only a new paradigm for bradyzoite biology but also develop the experimental methodologies to dissect bradyzoite replication we have been able to conclusively detect occurs challenging the existing dogma that bradyzoites are largely dormant entities. Our initial studies provide a new window into the dynamics of bradyzoite growth within tissue cysts which exhibit a level of complexity and sophistication that has not been previously appreciated. In this exploratory and developmental study we focus on the generation of new experimental approaches to directly interrogate and dissect the progression of the cell cycle within bradyzoites. Such insights would fill a vast gap in our knowledge that has stymied the development of treatments that are targeted toward the elimination of tissue cysts and bradyzoites. Targeting of tissue cysts and bradyzoites would eliminate the primary trigger of toxoplasmic encephalitis in the HIV-AIDS.

描述(申请人提供)：弓形体脑炎(TE)是艾滋病毒-艾滋病的一种，其定义是机会性感染，与慢性形式的TE感染有关，该感染由缓殖体介导，在中枢神经系统的组织囊内。尽管在这一过程中关于艾滋病毒-艾滋病相关弓形虫病的发病机制，人们对组织包囊的生物学及其所含寄生虫的缓殖子阶段知之甚少。在研究慢性期的进展以及在重新激活期间建立、维持和丧失潜伏期的机制方面，关键限制之一是无法对缓殖体在体内的生理和发育进行严格的洞察。为了消除这一主要限制，我们已经启动了一项全面的研究计划，通过开发直接解决体内组织囊内缓殖体复制的方法来了解缓殖体生物学。这些初步研究表明，缓殖子具有以前未被认识到的复制和新陈代谢能力，可以在开发药物中利用这种能力来针对传统上难以治疗的状态。通过这项研究，我们的目标不仅是建立一个新的缓殖体生物学范式，而且还开发出实验方法来解剖我们已经能够最终检测到的缓殖体复制发生，挑战现有的教条，即缓殖体在很大程度上是休眠实体。我们的初步研究为了解组织囊内缓殖子生长的动力学提供了一个新的窗口，它表现出以前没有意识到的复杂性和成熟度。在这项探索性和发育性研究中，我们专注于产生新的实验方法来直接询问和剖析缓殖子内细胞周期的进展。这种洞察力将填补我们知识中的一个巨大空白，这一空白阻碍了旨在消除组织囊肿和缓殖体的治疗方法的开发。以组织包囊和缓殖子为目标将消除艾滋病毒/艾滋病患者中弓形虫脑炎的主要诱因。