In-vitro brain organotypic model of Progressive Multifocal Leukoencephalopathy

进行性多灶性白质脑病的体外脑器官模型

• 批准号: 8437132
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 19.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437132
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Autoimmune Diseases; Biological; Biology; Brain; Cancer Patient; Cell Communication; Cell Culture Techniques; Cell Line; Cell model; Cells; Complication; DNA Viruses; Demyelinating Diseases; Development; Disease; Effectiveness; Environment; Epidemic; Epilepsy; Exhibits; Family; Genome; HIV; Human; Immunocompromised Host; Immunosuppressive Agents; In Vitro; Incidence; Infection; Integration Host Factors; JC Virus; Knowledge; Longitudinal Studies; Malignant Neoplasms; Modeling; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Neurobiology; Neuroglia; Neurologic; Neurons; Oligodendroglia; Operative Surgical Procedures; Opportunistic Infections; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Play; Polyomaviridae; Population; Predisposition; Process; Progressive Multifocal Leukoencephalopathy; Quality of life; Rare Diseases; Rheumatoid Arthritis; Role; Staging; Structure; System; Systemic Lupus Erythematosus; Testing; Tissue Model; Viral; Virus; Virus Diseases; base; brain cell; brain tissue; cell transformation; glial cell development; human embryonic stem cell; improved; in vitro Model; in vivo; natalizumab; progenitor; research study; response; tissue culture; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a devastating infection of the brain by JC virus, a virus that may remain dormant and inactive until its activation is triggered by immunological disturbances that produce immunosupression in humans. Patients affected by AIDS or immunosuppressive disorders such as cancer or rheumatological disorders are highly susceptible for developing PML. One of the most evident limiting factors in our lack of knowledge of the mechanisms of infection in PML is the lack of reliable in-vitro cell or tissue models for studying the pathobiology of JCV infection. This proposal directly addresses this critical desirable need for the development of an in-vitro brain tissue model of JCV infection. By taking advantage of surgically removed brain tissues from patients undergoing surgical treatment of epilepsy, we developed an in-vitro human organotypic brain tissue culture (HOBTC) system suitable for long-term studies of neuroglial cells, microvascular networks and neuronal-glial interactions. This proposal will further characterize the use of the in-vitro model of JCV infection in HOBTC to assess critical questions about the biology of JCV infection of neuroglia cells and cellular responses to infection, but most importantly to develop a model that may facilitate testing of potential approaches in the treatment of PML. We plan to characterize the profile of neuroglial cell responses to JCV infection in the HOBTC model and also to study the effects of HIV co-infection in the dynamic and patterns of neuroglia infection in the HOBTC model. We will study whether molecular differences and disarrangements in the JCV genome of viruses isolated from CSF of PML patients affect the dynamic and pattern of neuroglia infection in the HOBTC model. Our ability to develop an in-vitro tissue model of PML infection will improve the understanding of the biological mechanisms of JCV infection and above all identify viral and host factors that modulate and determine the pattern of infection of neuroglial cells within the CNS. That ability will also expedite the development of strategies to modify and control JCV infections and to eventually find specific treatments for PML.

描述（由申请人提供）：渐进的多灶性白细胞病原（PML）是JC病毒对大脑的毁灭性感染，JC病毒可能保持休眠状态和不活跃，直到其激活被免疫学扰动引起，从而在人类中产生免疫抑制。受艾滋病或免疫抑制疾病（例如癌症或流变学疾病）影响的患者非常容易发生PML。对于我们缺乏PML感染机制的知识，最明显的限制因素之一是缺乏可靠的体外细胞或组织模型来研究JCV感染的病理生物学。该提案直接解决了对JCV感染的体外脑组织模型发展的重要需求。通过利用接受癫痫手术治疗的患者的手术去除脑组织，我们开发了一种体外人体器官脑组织培养（HOBTC）系统，适用于对神经胶质细胞，微血管网络和神经元相互作用的长期研究。该提案将进一步表征JCV感染在HOBTC中的使用模型，以评估有关神经胶质细胞JCV感染的生物学的关键问题以及对感染的细胞反应，但最重要的是开发一种模型，该模型可以促进PML治疗中潜在方法的测试。我们计划表征HOBTC模型中神经胶质细胞对JCV感染的反应的特征，并研究HIV共感染在HOBTC模型中神经胶质感染动态和模式中的影响。我们将研究从PML患者CSF中分离出的病毒的JCV基因组中的分子差异和混乱是否会影响HOBTC模型中神经凝胶感染的动态和模式。我们开发PML感染的体外组织模型的能力将提高对JCV感染的生物学机制的理解，最重要的是，所有的病毒和宿主因子调节和确定CNS内神经细胞的感染模式。该能力还将加快制定修改和控制JCV感染的策略，并最终找到PML的特定治疗方法。

项目成果

A human-derived 3D brain organoid model to study JC virus infection.

• DOI: 10.1007/s13365-022-01062-7
• 发表时间: 2022-03
• 期刊: Journal of neurovirology
• 影响因子: 3.2
• 作者: Barreras P;Pamies D;Monaco MC;Muñoz LS;Zhong X;Major EO;Hogberg HT;Hartung T;Pardo CA
• 通讯作者: Pardo CA