Brain pathology and function in a chronic mouse model of ZIKV transmission

ZIKV 慢性传播小鼠模型的脑病理学和功能

• 批准号: 10605175
• 负责人: Alysson R. Muotri
• 金额: $ 65.49万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605175
• 关键词: Ablation; Adult; Aedes; Affect; Americas; Animals; Antimalarials; Area; Basic Science; Biochemistry; Biological; Birth; Bite; Brain; Brain Pathology; Categories; Chemical Structure; Child; Chloroquine; Chronic; Cognitive deficits; Coitus; Combined Modality Therapy; Congenital Abnormality; Consensus; Cortical Malformation; Culicidae; Data; Development; Diagnostic Procedure; Discipline; Drops; Drug Design; Dyskinetic syndrome; Epidemic; Exposure to; Eye; Eye Development; FDA approved; Female; Fetus; Flavivirus; Functional disorder; Guillain Barré Syndrome; HIV/HCV; Head circumference; Human; Human body; Imaging Techniques; Infection; Interferons; Lead; Left; Life Cycle Stages; Link; Long-Term Effects; Macaca; Magnetic Resonance; Medical; Medicine; Methodology; Microcephaly; Microscopy; Modeling; Molecular; Mothers; Mus; Neuroimmune; Neurologic; Neurologic Dysfunctions; Neuromuscular Junction; Newborn Infant; Pathology; Peptide Hydrolases; Perinatal; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Preventive; Proliferating; Prophylactic treatment; Proteins; Proteome; Public Health; Reporting; Research; Research Project Grants; Research Proposals; Resistance; Rodent; SJL Mouse; Seminal fluid; Sensory; Sexual Transmission; Sexual transmission of Zika; Structure; Talents; Teratogenic effects; Therapeutic; Thick; Treatment Protocols; Vertical Transmission; Viral; Virus; Virus Diseases; Wild Type Mouse; ZIKV infection; Zika Virus; Zika virus vaccine; acute infection; behavioral outcome; chronic infection; cognitive change; congenital zika syndrome; design; drug development; early life exposure; experience; fetal; fetal infection; in silico; in utero; in vivo; inhibitor; insight; knockout animal; male; mouse model; multidisciplinary; nerve stem cell; neuropathology; offspring; pathogenic virus; pharmacologic; postnatal; pregnant; prevent; pup; skills; small molecule; statistics; stem cell biology; success; transcription factor; transmission process; ultrasound; virology

Project Summary Zika virus (ZIKV) is primarily transmitted to people through the bite of an infected mosquito from the Aedes genus, mainly Aedes aegypti, although the virus can also be transmitted through sexual intercourse. There is scientific consensus that ZIKV is a causative agent of microcephaly, a birth defect in children born to infected mothers and neuroimmune Guillain-Barré syndrome in infected adults. Even more troubling, vertical transmission of ZIKV is not limited to microcephaly alone, but it is now directly linked to multiple, albeit still severe, dysfunctions in the development of the brain and the eyes, called the Congenital Zika Syndrome. Because ZIKV continues to spread through the Americas, a better understanding of ZIKV pathology along with an efficient means to treat the infection is urgently needed. Accordingly, the focus of our MPI research proposal is to greatly increase our understanding of the changes to brain pathology caused by long-term ZIKV infections, and a practical means to control the virus in a pharmacologically-beneficial manner by repurposing the current FDA-approved anti-viral and anti-malarial pharmaceuticals as cocktails. Importantly, a physiologically-relevant SJL mouse model of ZIKV vertical transmission and chronic infection is employed in our in-depth studies, rather than interferon-knockout animals that perish in a few days post-infection. This project is firmly grounded on volumes of our preliminary data. Our Specific Aims are: (1) Determine the dynamics of fetal brain infection and investigate perinatal consequences following ZIKV vertical transmission in SJL mice, (2) Determine structural and functional consequences to the adult brain following congenital ZIKV infection in SJL mice, and (3) Determine the best treatment regimens for ZIKV infection using inhibitors of different stages of the viral life cycle and their combinations to prevent vertical transmission of ZIKV. Our exceptional and well-balanced multidisciplinary team includes experienced professionals with complementary expertise in the diverse areas of virology, biochemistry, neuro- and stem cell biology, drug design, in silico modeling and statistics, brain development and magnetic resonance microscopy. To accomplish our interrelated Specific Aims in their entirety and in a timely fashion, we will use a plethora of the advanced cellular, molecular and imaging techniques and methodologies which, especially if combined, are not readily available for many others. An additional advantage of our multi-talented team is our extensive, decade-long, studies in flaviviruses. Because our ZIKV-centered research has been already on-going for over a 2-year period, we have already acquired significant momentum in our studies that bodes well for the success of this proposed research project.

项目摘要 寨卡病毒（ZIKV）主要通过伊蚊叮咬受感染的蚊子传播给人 埃及伊蚊属，主要是埃及伊蚊，虽然病毒也可以通过性交传播。有 科学界一致认为ZIKV是小头畸形的病原体，小头畸形是一种出生缺陷， 母亲和神经免疫格林-巴利综合征感染的成年人。更麻烦的是，垂直 ZIKV的传播不仅限于小头畸形，但它现在直接与多种，尽管仍然 严重的，大脑和眼睛发育功能障碍，称为先天性寨卡综合征。 由于ZIKV继续在美洲传播，因此更好地了解ZIKV病理沿着 迫切需要一种治疗感染的有效方法。因此，我们MPI研究的重点是 该提案旨在大大增加我们对长期ZIKV引起的大脑病理学变化的理解 感染，以及通过重新利用以药理学有益的方式控制病毒的实用方法 目前FDA批准的抗病毒和抗疟疾药物作为鸡尾酒。重要的是 采用ZIKV垂直传播和慢性感染的生理学相关的SJL小鼠模型， 我们的深入研究，而不是干扰素敲除动物在感染后几天内死亡。这 这个项目是建立在我们大量的初步数据基础上的。我们的具体目标是：（1）确定 胎儿脑感染的动力学，并调查ZIKV垂直传播后的围产期后果， （2）确定先天性ZIKV后成年脑的结构和功能后果 （3）使用ZIKV抑制剂确定ZIKV感染的最佳治疗方案， 病毒生命周期的不同阶段及其组合，以防止ZIKV的垂直传播。我们 一个卓越和平衡的多学科团队，包括经验丰富的专业人士， 在病毒学、生物化学、神经和干细胞生物学、药物设计、计算机模拟等不同领域的专业知识 建模和统计，大脑发育和磁共振显微镜。完成我们 在他们的整体和及时的方式相互关联的具体目标，我们将使用大量的先进的 细胞、分子和成像技术和方法，特别是如果结合起来， 可用于许多其他人。我们多才多艺的团队的另一个优势是我们广泛的，长达十年的， 黄病毒的研究因为我们以ZIKV为中心的研究已经持续了两年多 在此期间，我们已经在我们的研究中获得了巨大的动力，这预示着这项研究的成功。 建议的研究项目。