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: 8329124
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 23万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329124
• 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. PUBLIC HEALTH RELEVANCE: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal infection of the brain produced by the JC virus, a virus that may remain dormant in humans until activation produced by immunosupression. The mechanisms and modes of invasion of the brain and remain unknown due to the lack of in-vitro models. This proposal focuses on the development of an in-vitro organotypic brain tissue culture system to study the mechanisms of JCV infection of brain cells and for testing potential strategies for treatment PML.

描述(申请人提供)：进行性多灶性白质脑病(PML)是一种由JC病毒对大脑的毁灭性感染，JC病毒可能处于休眠和不活跃状态，直到其激活被免疫紊乱触发，从而在人类中产生免疫抑制。受艾滋病或免疫抑制疾病影响的患者，如癌症或风湿病，极易患上PML。我们对PML感染机制缺乏了解的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。这一建议直接解决了开发JCV感染的体外脑组织模型的关键的可取需求。通过利用手术切除的癫痫患者的脑组织，我们开发了一种适合于神经胶质细胞、微血管网络和神经元-胶质细胞相互作用的长期研究的体外人类器官型脑组织培养系统(HOBTC)。这项建议将进一步表征HOBTC中JCV感染的体外模型的使用，以评估关于JCV感染的神经胶质细胞生物学和细胞对感染的反应的关键问题，但最重要的是开发一种可能有助于测试PML治疗的潜在方法的模型。我们计划在HOBTC模型中表征神经胶质细胞对JCV感染的反应，并在HOBTC模型中研究HIV混合感染对神经胶质细胞感染的动态和模式的影响。我们将研究从PML患者脑脊液中分离的病毒JCV基因组的分子差异和错位是否会影响HOBTC模型中神经胶质细胞感染的动态和模式。我们建立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，最重要的是识别调节和决定CNS内神经胶质细胞感染模式的病毒和宿主因素。这一能力还将加快制定战略，以改变和控制JCV感染，并最终找到治疗PML的具体方法。 公共卫生相关性：进行性多灶性白质脑病(PML)是一种罕见但致命的脑部感染，由JC病毒引起，这种病毒可能在人类体内处于休眠状态，直到免疫抑制产生激活为止。由于缺乏体外模型，侵袭大脑的机制和模式仍不清楚。这项建议侧重于发展体外器官型脑组织培养系统，以研究JCV感染脑细胞的机制，并测试治疗PML的可能策略。