Translational applications of Progressive Multifocal Leukoencephalopathy studies

进行性多灶性白质脑病研究的转化应用

• 批准号: 8046315
• 负责人: Igor J Koralnik
• 金额: $ 14.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046315
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Transfer; Alleles; Allografting; Antigen-Presenting Cells; Antiviral Agents; Astrocytoma; BK Virus; Blood; Bone Marrow; Bone Marrow Cells; Brain; CD8B1 gene; Case Study; Cells; Clinical; Clinical Research; Communicable Diseases; Crohn' s disease; Cytotoxic T-Lymphocytes; DNA Sequence Rearrangement; Demyelinating Diseases; Dendritic Cells; Detection; Diagnosis; Diagnostic; Disease; Disease Marker; Evolution; Faculty; Genetic; Genotype; HIV; Hematologic Neoplasms; Hematology; Highly Active Antiretroviral Therapy; Histocompatibility Antigens Class I; Histology; Human; Immune response; Immunology; Immunomodulators; Immunosuppression; Immunotherapy; Incidence; Individual; Infection; Inflammation; Integration Host Factors; Integrin alpha4beta1; Interferons; JC Virus; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Laboratories; Lead; Lesion; Lymphocyte; MHC Class I Genes; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Marketing; Mentors; Metabolic Marker; Molecular; Multiple Sclerosis; Names; Nature; Nephrology; Neurologic; Neurology; Neurons; Nucleic Acid Regulatory Sequences; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathology; Patients; Peptides; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Physiologic pulse; Play; Polyomavirus; Populations at Risk; Principal Investigator; Prognostic Marker; Progressive Multifocal Leukoencephalopathy; Protons; Reporting; Research Personnel; Risk; Role; Scientist; Shock; Students; Symptoms; T-Lymphocyte; Therapeutic; Time; Tissues; Training; Translating; Transplant Recipients; Tysabri; Variant; Viral; Viral Load result; Viremia; Virus; Virus Diseases; avonex; base; career; disorder prevention; granule cell; immunosuppressed; insight; interest; natalizumab; neuroimaging; next generation; novel; patient oriented; patient oriented research; prevent; programs; reactivation from latency; research study; tool; trafficking; tumor; virology

DESCRIPTION (provided by applicant): Progressive Multifocal Leukoencephalopathy (PML) is a deadly opportunistic infection of the brain caused by the polyomavirus JC (JCV), which occurs in immunosuppressed individuals. There is no treatment for PML, and the incidence of this disease has not decreased significantly in HIV+ patients since the availability of highly active antiretroviral therapy (HAART). In addition, a growing number of organ transplant recipients are also at risk for PML, as well as patients with multiple sclerosis and Crohn's disease treated with the novel immunomodulatory medication natalizumab. The challenges that lies ahead is to harness advances in our understanding of the virological and immunological determinants of JCV pathogenesis and translate them into both pre-diagnostic markers aiming at preventing PML, as well as therapeutic options for this disease, while training the next generation of young physicians in patient-oriented research. In this application, we will: 1) Characterize pre-diagnostic markers of PML; 2) Analyze the molecular determinants of JCV latency and reactivation in bone marrow, and determine the phenotype of JCV infected bone marrow cells; 3) Determine the role of HLA class I alleles in PML outcome; 4) Correlate MRI/1H-MRS, histological, immunological and virological parameters over time with lesion volume, neurological deficit and clinical outcome of the PML patients; 5) Study JCV reactivation in MS patients treated with natalizumab, and explore the effect of VLA-4 blockade on JCV-specific CD8+ T cells; 6) Characterize the pathogenesis of the JCV variant associated with JCV Granule Cell Neuronopathy (JCV GCN); 7) Develop dendritic cell-based immunotherapy for PML; and 8) Explore the antiviral immune response against the polyomavirus BK in the context of HLA mismatched kidney grafts. Opportunities for mentoring young physicians, scientists, junior faculty and students are discussed for each specific aim. These studies will certainly appeal to young individuals interested to launch their careers in the fields of Neurology, Neurolmaging, Infectious Diseases, Virology, Immunology, Hematology, Nephrology and Pathology.

描述（由申请人提供）：进行性多灶性白质脑病（PML）是由多瘤病毒 JC（JCV）引起的致命性脑部机会性感染，发生在免疫抑制个体中。 PML 尚无治疗方法，而且自高效抗逆转录病毒疗法 (HAART) 出现以来，HIV + 患者中这种疾病的发病率并未显着下降。此外，越来越多的器官移植受者以及接受新型免疫调节药物那他珠单抗治疗的多发性硬化症和克罗恩病患者也面临着 PML 的风险。未来的挑战是利用我们对 JCV 发病机制的病毒学和免疫学决定因素的理解进展，并将其转化为旨在预防 PML 的预诊断标志物以及该疾病的治疗方案，同时培训下一代年轻医生从事以患者为导向的研究。在此应用中，我们将： 1) 表征 PML 的预诊断标志物； 2）分析JCV在骨髓中潜伏和重新激活的分子决定因素，并确定JCV感染的骨髓细胞的表型； 3) 确定HLA I类等位基因在PML结果中的作用； 4) 将 MRI/1H-MRS、组织学、免疫学和病毒学参数随时间的变化与 PML 患者的病灶体积、神经功能缺损和临床结果相关联； 5）研究那他珠单抗治疗的MS患者的JCV再激活，探讨VLA-4阻断对JCV特异性CD8+ T细胞的影响； 6) 表征与 JCV 颗粒细胞神经元病 (JCV GCN) 相关的 JCV 变异的发病机制； 7）开发基于树突状细胞的PML免疫疗法； 8) 探索 HLA 不匹配肾移植背景下针对多瘤病毒 BK 的抗病毒免疫反应。针对每个具体目标，讨论了指导年轻医生、科学家、初级教师和学生的机会。这些研究肯定会吸引有兴趣在神经病学、神经影像学、传染病、病毒学、免疫学、血液学、肾病学和病理学领域开展职业生涯的年轻人。