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Disease Mechanisms of Pontocerebellar Hypoplasia Type 10

10 型脑桥小脑发育不全的疾病机制

基本信息

批准号：
10428653
负责人：
Ashleigh E Schaffer
金额：
$ 51.86万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10428653
关键词：
Affect Alleles Animal Model Animals Ataxia Behavioral Binding Biogenesis Brain Brain Diseases Cell model Cessation of life Childhood Clinical Cognitive DNA Sequence Alteration Data Defect Dermal Disease Disease Progression Disease model Electrophysiology (science)Etiology Event Fibroblasts Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals High-Throughput Nucleotide Sequencing Histology Human Immunohistochemistry Impaired cognition In Vitro Individual Inherited Knock-out Knowledge Lead Life Light Measures Mediating Messenger RNA Modeling Molecular Molecular Profiling Motor Motor Neuron Disease Motor Neurons Mus Mutant Strains Mice Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Onset of illness Pathogenesis Pathogenicity Pathology Patients Pattern Peripheral Nervous System Phenotype Phosphotransferases Physiological Polyadenylation Pontocerebellar hypoplasia Pre-Clinical Model Prevalence Protein Isoforms RNA RNA Processing RNA-Binding Proteins Refractory Repression Resources Role Seizures Spinal Spinal Cord Structure System Testing Therapeutic Tissues Transfer RNA Variant aged base causal variant disease phenotype effective therapy gain of function gene therapy genetic manipulation human disease human stem cells in vivo induced pluripotent stem cell innovation molecular phenotype motor behavior motor deficit motor disorder motor impairment motor neuron degeneration mouse genetics mutant mouse model nervous system disorder neuron development novel overexpression prevent protein function spasticity therapeutic target tool transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Degeneration of brain or spinal cord neurons is associated with many untreatable neurological disorders and leads to a gradual decline in cognitive and motor function, and eventual death. While more prevalent in aged individuals, neurodegenerative disease onset is variable and can begin in childhood. There are no effective therapies for the majority of patients, likely due to our limited understanding of disease etiology. Inherited neurodegenerative disorders are commonly caused by genetic mutations in RNA binding proteins that regulate RNA biogenesis. In order to develop therapeutics for this class of disorders, it will be critical to understand how RNA binding proteins function in normal and diseased states, and whether molecular changes are amenable to correction. Our preliminary data suggests mRNA processing may be significantly affected in cases of inherited childhood motor neuron degeneration. To test our hypothesis that mRNA processing defects cause pediatric motor neuron disease, we have created human stem cell- and animal-based models to correlate molecular changes with disease pathology. We will apply high-throughput sequencing, electrophysiology, histology and behavioral approaches to our novel disease models to pinpoint pathogenic transcriptional mRNA isoforms expressed as a consequence of the RNA binding protein mutation as well as test a candidate targeted gene- based therapy.

项目总结/文摘