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Role of viral infections in potassium channel-related cerebellar ataxia

病毒感染在钾通道相关小脑共济失调中的作用

基本信息

批准号：
10183352
负责人：
AKIKO IWASAKI
金额：
$ 54.02万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183352
关键词：
Adaptor Signaling Protein Address Affect Aftercare Aging Animal Model Animals Antiviral Agents Ataxia Atrophic Autophagocytosis Binding Biochemical Biological Biological Assay Birth Brain Cell Death Cell Survival Cell membrane Cell model Cell physiology Cells Cerebellar Ataxia Cerebellar degeneration Cerebellum Cessation of life Couples DNA Sequence Alteration Data Defense Mechanisms Dependence Development Developmental Delay Disorders Disease Distal Electroencephalography Enzymes Etiology Exposure to Family Functional disorder Genes Genetic Genital Genitalia Goals Healthcare Systems Human IFNAR1 gene Immune Impairment Individual Inflammation Influenza A virus Interferon Type I Interferon-alpha Interferon-beta Interferons Ion Channel Ions Kinetics Lead Life Light Link Locomotion Longevity Measurement Molecular Molecular Probes Mucous Membrane Multivesicular Body Mus Mutant Strains Mice Mutation Neurobiology Neurodegenerative Disorders Neurons Onset of illness Patch-Clamp Techniques Pathway interactions Point Mutation Potassium Channel Property Proteins Purkinje Cells Recombinant Interferon Respiratory System Role Signal Pathway Signal Transduction Simplexvirus Site-Directed Mutagenesis Slice Small Interfering RNA Spinocerebellar Ataxias Symptoms TANK-binding kinase 1 Testing Toll-like receptors Vesicular stomatitis Indiana virus Viral Virus Diseases base cellular pathology cytokine disease-causing mutation early onset effective therapy experimental study middle age motor disorder motor symptom mutant novel therapeutic intervention pathogen premature response stressor type I interferon receptor voltage

项目摘要

Cerebellar ataxia is a progressive neurodegenerative disease with major impact on the daily life of affected people, their families, and, on the health care system. There is no cure for cerebellar ataxia regardless of its origin. There is no effective treatment to slow the progression of symptoms that frequently lead to premature death. Ion channels have been implicated in the etiology of several form of cerebellar ataxia. For example, specific mutations in KCNC3, the gene encoding the Kv3.3 channel, such as the G592R point mutation, have been identified as the underlying genetic cause of late-onset spinocerebellar ataxia. Despite of these developments, there is no understanding of why late-onset cerebellar ataxias emerge in some but not all subjects with genetic mutations. There is also great variability in when during the lifespan of the affected subjects the symptoms emerge. Based on our unexpected preliminary observations, we hypothesize that disease onset in genetically vulnerable subjects is determined by host-pathogen interactions with particular emphasis on viral infections. Specifically, we assert that the synergistic activation of an intracellular signaling pathway that is targeted by both the mutant potassium channel and by viral defense mechanisms, impairs cellular function and results in the death of Purkinje cells. Our hypothesis and preliminary data challenge contemporary views on the etiology of cerebellar ataxia with implications for novel therapeutic strategies. We will test our hypothesis using cellular- and animal models with state-of-the-art neurobiological, molecular biological and immunobiological approaches.

小脑性共济失调是一种进行性神经退行性疾病，严重影响患者的日常生活