Toxoplasma gondii Regulation of Host GABAergic Signaling

弓形虫对宿主 GABA 信号传导的调节

基本信息

批准号：
9212770
负责人：
Ira J Blader
金额：
$ 55.3万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212770
关键词：
Acquired Immunodeficiency Syndrome Address Affect Antibodies Architecture Astrocytes Blood - brain barrier anatomy Brain Cancer Patient Cells Communicable Diseases Complication Data Defect Disease Electron Microscopy Elements Encephalitis Encephalopathies Enzymes Epilepsy Exhibits Fetus Functional disorder Genes Genetic Genetic Screening Glutamates Goals Growth Health Homeostasis Hypersensitivity Immune Immune response Immunocompromised Host Immunohistochemistry Immunology Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Inhibitory Synapse Interneurons Label Life Link Maintenance Mediating Messenger RNA Microglia Molecular Morphology Mus Neuraxis Neurologic Neurons Neurosciences Parasite Control Parasites Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phenotype Population Predisposition Presynaptic Terminals Proteins Quantitative Trait Loci Regulation Reporter Role Seizures Signal Transduction Site Structure Symptoms Synapses Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Work base cytokine gamma-Aminobutyric Acid genetic approach immune function in utero inhibitory neuron mouse model neural circuit neuronal circuitry neurotransmission novel therapeutics presynaptic public health relevance therapy development

项目摘要

DESCRIPTION (provided by applicant): Seizures are a common and life-threatening complication of individuals suffering from infections and inflammation in the central nervous system. In these individuals, seizures develop due to a variety of reasons including breakdown of the blood-brain barrier, changes in ionic homeostasis, and/or increased abundance of inflammatory proteins such as cytokines and antibodies. But, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. The protozoan parasite Toxoplasma gondii infects approximately one-third of the world's population. Most people are asymptomatic because the parasite resides latently within brain and other tissues. But individuals who are immunocompromised or are infected in utero develop toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated leading immune-mediated tissue destruction. If reactivation occurs in the brain, the resulting toxoplasmic encephalitis presents with a variety of neurological sequelae that includes seizures. Using a murine model for toxoplasmic encephalitis our data indicates that Toxoplasma specifically alters the distribution of key proteins that localie to GABAergic synapses. This change in GABAergic synaptic connectivity causes the mice to develop seizures because these synapses are critical for controlling the flow and timing of information transfer in the brain. This work will define how these proteins are mislocalized (Aim 1), determine the role of inflammatory cells in GABAergic protein mislocalization (Aim 2), and identify the parasite factors that affect GABAergic protein localization and onset of seizures (Aim3). The long-term goal of this work is to determine how seizures develop in Toxoplasma-infected individuals and use this information to generate novel therapies to treat these patients and others suffering from infection-induced seizures.

描述（由适用提供）：癫痫发作是患有中枢神经系统感染和感染的个体的常见且威胁生命的并发症。在这些个体中，由于多种原因而出现癫痫发作，包括细分血脑屏障，离子稳态的变化和/或增加炎症蛋白的抽象增加，例如细胞因子和抗体。但是，大脑中的这些变化如何改变引起癫痫样活动的突触接线和神经传递，这在很大程度上尚不清楚。原生动物的寄生虫弓形虫感染了世界人群的三分之一。大多数人是不对称的，因为寄生虫在大脑和其他组织内部潜在。但是，当寄生虫重新激活并且宿主免疫响应无法控制寄生虫复制或失调的领先的免疫介导的组织破坏时，当寄生虫重新激活并且宿主免疫响应后，被免疫功能低下或感染了子宫内发育型弓形虫病。如果重新激活发生在大脑中，则由此产生的弓形虫脑炎呈现多种使用用于毒质性脑炎的鼠模型，我们的数据表明，毒品特异性改变了与GABA能突触的关键蛋白的分布。 GABA能突触连通性的这种变化导致小鼠发作癫痫发作，因为这些突触对于控制大脑中信息传递的流量和时间至关重要。这项工作将定义这些蛋白如何被误定量（AIM 1），确定炎症细胞在GABA能蛋白错误定位中的作用（AIM 2），并确定影响GABA能蛋白定位和癫痫发作的寄生虫因子（AIM3）。这项工作的长期目标是确定弓形虫感染的个体中的癫痫发作，并使用这些信息来产生新的疗法来治疗这些患者以及其他患有感染引起的癫痫发作的患者。