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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.