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Immune modulation and CNS pathology following exogenous ?-synuclein challenge

外源性 α-突触核蛋白攻击后的免疫调节和 CNS 病理学

基本信息

批准号：
9388125
负责人：
PARAMITA CHAKRABARTY
金额：
$ 22.59万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9388125
关键词：
Adaptive Immune System Amyloid Antigen Presentation Antigens Appearance Attenuated Bolus Infusion Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Cellular Immunity Characteristics Chronic Communication Complex Data Disease Epigenetic Process Epitopes Etiology Exocytosis Flow Cytometry Freund&apos s Adjuvant Future Gastritis Genes Goals Hindlimb Human Immune Immune Sera Immune response Immune signaling Immune system Immunity Immunodeficient Mouse Immunotherapy Infection Inflammatory Injectable Injection of therapeutic agent Intraperitoneal Injections Knockout Mice Laboratories Lead Length Lewy Body Dementia Lewy Body Disease Light Lymphoid Mature B-Lymphocyte Mediating Mus Mutation Myeloid Cells Nature Nervous System Heredodegenerative Disorders Nervous system structure Neurodegenerative Disorders Neuroimmune Neurons Oligodendroglia Organ Outcome Outcome Measure Paralysed Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Peripheral Nervous System Play Preventive Property Proteins Rag1 Mouse Regulation Reporting Research Personnel Rodent Model Role Seeds Spinal Cord Spinal Injections Study models Substantia nigra structure Synaptic Vesicles T-Lymphocyte Testing Time Transgenic Mice Transgenic Organisms alpha synuclein base experience experimental study feeding histological studies immune activation immunogenic immunoregulation influenzavirus insight mouse model nano-string neurodegenerative dementia neuron loss neurotoxicity novel preconditioning prion-like proteostasis synuclein synucleinopathy transmission process white matter

项目摘要

Progressive accumulation of intracellular inclusions of α-synuclein protein in the nervous system is a characteristic feature of Lewy Body diseases which is part of a spectrum of sporadic and hereditary neurodegenerative diseases termed α- synucleinopathies. The definitive involvement of α-synuclein in the etiology of these disorders was established by the findings that mutations in α-synuclein can directly cause Lewy body dementia. Many studies suggest that the progressive spread of α-synuclein pathology in the peripheral nervous system and the brain occurs through direct α-synuclein transmission between cells. However, there is a major gap in our understanding of the epigenetic factors that modulate such prionoid properties of α-synuclein. Our preliminary data suggests that α-synuclein is an immunogenic protein and that additional factors, such as activation of cellular immunity, may contribute to the prionoid propagation of peripherally administered exogenous α-synuclein to the CNS of mice. To provide novel insights into immune-mediated mechanisms involved in induction of CNS α-synuclein inclusion pathology following peripheral challenge with exogenous α-synuclein, we have assembled a team of experienced investigators with diverse and unique expertise in α-synuclein proteostasis and neuroimmune regulation. In Aim 1, we will determine whether inflammatory preconditioning of peripheral immune milieu exacerbates induction and CNS transmission of α-synuclein pathology following peripheral challenge with exogenous α- synuclein fibrils. In Aim 2, we will test whether the prionoid properties of α-synuclein fibrils is suppressed in two independent lines of immunodeficient α-synuclein transgenic mice. Our study will inform us on the interplay between α- synuclein seeding and propagation and cellular immunity. We expect our study to be highly translational as it will clarify 1) potential interactions between α-synuclein and cellular immunity and further help us 2) devise preventive immunobiotherapies strategies to slow down intercellular α-synuclein pathogenesis in the future.

神经系统细胞内α-突触核蛋白包涵体的渐进性积累是一个特征性特征