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: 9891111
• 负责人: Alysson R. Muotri
• 金额: $ 65.48万
• 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/9891111
• 关键词: Adult; Aedes; Affect; Americas; Animals; Antimalarials; Antiviral Agents; Area; Basic Science; Biochemistry; Biological; Birth; Bite; Brain; Brain Pathology; Categories; Chemical Structure; Child; Chloroquine; Chronic; Cognitive deficits; Coitus; 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; Life Cycle Stages; Link; Long-Term Effects; Macaca; Magnetic Resonance; Malaria; Medical; Methodology; Microcephaly; Microscopy; Modeling; Mothers; Mus; Neuroimmune; Neurologic; Neurologic Dysfunctions; Neuromuscular Junction; Newborn Infant; Pathology; Peptide Hydrolases; Perinatal; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; 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; Time; Treatment Protocols; Ultrasonography; Vertical Disease 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; experience; fetal; fetal infection; in silico; in utero; in vivo; inhibitor/antagonist; insight; knockout animal; male; molecular imaging; mouse model; multidisciplinary; nerve stem cell; offspring; pathogenic virus; postnatal; pregnant; prevent; pup; small molecule; statistics; stem cell biology; success; transcription factor; transmission process; viral transmission; 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.

项目概要 寨卡病毒 (ZIKV) 主要通过受感染的伊蚊叮咬传播给人类 属，主要是埃及伊蚊，尽管该病毒也可以通过性交传播。有 科学界一致认为寨卡病毒是小头畸形的病原体，小头畸形是感染者所生儿童的先天缺陷 母亲和感染成人的神经免疫吉兰-巴利综合征。更麻烦的是，垂直 ZIKV 的传播不仅限于小头畸形，而且现在与多种疾病直接相关，尽管仍然如此 严重的大脑和眼睛发育功能障碍，称为先天性寨卡综合症。 由于 ZIKV 继续在美洲传播，因此需要更好地了解 ZIKV 病理学 迫切需要一种有效的方法来治疗这种感染。因此，我们 MPI 研究的重点 提议是为了大大增加我们对长期 ZIKV 引起的大脑病理变化的了解 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为鸡尾酒药物。重要的是，一个 采用 ZIKV 垂直传播和慢性感染的生理相关 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 该项目牢固地建立在我们大量的初步数据的基础上。我们的具体目标是： (1) 确定 胎儿脑部感染动态并调查 ZIKV 垂直传播后的围产期后果 SJL 小鼠，(2) 确定先天性 ZIKV 后对成年大脑的结构和功能影响 (3) 使用抑制剂确定 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。我们的 卓越且均衡的多学科团队包括经验丰富的专业人士，具有互补性 病毒学、生物化学、神经和干细胞生物学、药物设计、计算机模拟等多个领域的专业知识 建模和统计、大脑发育和磁共振显微镜。为了完成我们的 为了全面、及时地实现相互关联的具体目标，我们将使用大量先进的技术 细胞、分子和成像技术和方法，尤其是组合起来，并不容易 可供许多其他人使用。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，我们的研究已经取得了巨大的进展，这预示着这一项目的成功 拟议的研究项目。