Investigation and Treatment of Undiagnosed Neuroinflammatory Diseases

未确诊的神经炎症性疾病的调查和治疗

• 批准号: 10403644
• 负责人: Nischay Mishra
• 金额: $ 58.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403644
• 关键词: Admission activity; Affect; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Bacteria; Bioinformatics; Biological Assay; Biological Markers; Biological Products; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Chronic; Classification; Clinical; Communicable Diseases; Communities; Complex; Dangerousness; Databases; Development; Diagnosis; Diagnostic; Disease; Encephalitis; Enrollment; Etiology; Evaluation; Extramural Activities; Failure; Fc Receptor; Flow Cytometry; Functional disorder; Government; Health care facility; Hospitalization; Human; Image; Immune; Immune response; Immunoprecipitation; Immunosuppressive Agents; In Vitro; Individual; Infection; Inflammatory; Institution; Investigation; Investigational Therapies; Knockout Mice; Laboratories; Lead; Libraries; Lymphocyte; MRI Scans; Malignant Neoplasms; Mass Spectrum Analysis; Medical center; Memory; Meningitis; Metagenomics; Methodology; Modeling; Molecular Biology; Morbidity - disease rate; Multicenter Studies; N-Methyl-D-Aspartate Receptors; Neuraxis; Neuroimmune; Neurologist; Neurology; Nucleic Acids; Parasites; Pathogen detection; Pathogenesis; Patients; Pattern; Persons; Phage Display; Phage ImmunoPrecipitation Sequencing; Physicians; Population Surveillance; Progressive Multifocal Leukoencephalopathy; Proteome; Protocols documentation; Psychoses; Recording of previous events; Reporting; Research; Scientist; Seizures; Services; Stains; Structure; Syndrome; T Chain; T cell clonality; T cell receptor repertoire sequencing; T-Lymphocyte; Techniques; Testing; Time; Tissue Stains; United States National Institutes of Health; Universities; Vertebrate Viruses; Viral; Virus; Washington; Yeasts; antibody detection; antibody test; antimicrobial; base; bioinformatics tool; career; cerebrospinal fluid flow; clinical center; clinical phenotype; collaborative approach; detection assay; detection method; disease diagnostic; fungus; genome sequencing; individual patient; microbial; mortality; nervous system disorder; neuroinflammation; next generation sequencing; novel; nucleic acid detection; pathogen; patient screening; predictive modeling; programmed cell death protein 1; programs; rare genetic disorder; relating to nervous system; targeted treatment; tertiary care; tool; virome; whole genome

PROJECT SUMMARY Of all neurological diseases, the neuroinflammatory diseases are the most challenging. Many of these remain undiagnosed and are a major cause of morbidity and mortality. Several studies have shown that nearly a third of the patients on the neurology service at any tertiary care facility have undiagnosed neuroimmune diseases, many of whom have prolonged hospitalizations over several months and nearly a third of these patients die from the illness during this admission. These patients often undergo extensive investigations and multiple empirical therapies with poor results. They also bounce between physicians and major medical centers undergoing repeated investigations with no additional benefit. It is critically necessary that we develop a structured program to diagnose these patients, properly classify these disorders and develop a rational approach to treatment. Comprehensively investigating individual patients cannot only clarify their underlying diagnosis and lead to more directed therapies, but it can also fundamentally alter how we treat a neuroinflammatory disease more generally. For example, we discovered elevated PD-1 levels on lymphocytes in CSF of patients with progressive multifocal leukoencephalopathy which led to the development of a novel treatment for this otherwise fatal illness. Despite these efforts by individual laboratories, many cases still remain undiagnosed and untreated. This intramural and extramural highly collaborative proposal brings together for the first time physician-scientists and scientists across top academic and government institutions who have dedicated their careers to developing deep clinical phenotyping protocols for patients with idiopathic neuroinflammatory diseases as well as high-throughput and comprehensive tools for identifying microbial nucleic acid in the central nervous system, viral and autoantibody antibody profiling in the cerebrospinal fluid, immune cell profiling and T-cell antigen profiling. These investigations will not only lead to the identification of novel diseases in individual patients but also serve as a model for how neuroinflammatory diseases can be deciphered more widely.

项目摘要 在所有神经系统疾病中，神经炎性疾病是最具挑战性的。其中许多疾病仍未得到诊断，是发病率和死亡率的主要原因。一些研究表明，在任何三级医疗机构的神经病学服务中，近三分之一的患者患有未诊断的神经免疫疾病，其中许多人延长了数月的住院时间，近三分之一的患者在住院期间死于这种疾病。这些患者经常接受广泛的调查和多种经验性治疗，结果不佳。他们还在医生和主要的医疗中心之间来回奔波，反复进行调查，没有额外的好处。这是非常必要的，我们开发一个结构化的程序来诊断这些患者，正确分类这些疾病，并制定一个合理的治疗方法。 全面调查个体患者不仅可以澄清他们的潜在诊断并导致更有针对性的治疗，而且还可以从根本上改变我们更普遍地治疗神经炎性疾病的方式。例如，我们发现进行性多灶性白质脑病患者CSF中淋巴细胞上的PD-1水平升高，这导致了对这种致命疾病的新治疗的开发。尽管各实验室作出了这些努力，但许多病例仍未得到诊断和治疗。 这项校内和校外高度合作的提案首次汇集了顶尖学术和政府机构的医生-科学家和科学家，他们致力于为特发性神经炎性疾病患者开发深入的临床表型分析方案，以及用于识别中枢神经系统中微生物核酸的高通量和综合工具，脑脊液中的病毒和自身抗体分析、免疫细胞分析和T细胞抗原分析。这些研究不仅可以识别个体患者的新疾病，还可以作为如何更广泛地解释神经炎性疾病的模型。