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A whole body model of Pol III-related leukodystrophy

Pol III相关脑白质营养不良的全身模型

基本信息

批准号：
10287751
负责人：
Robyn Moir
金额：
$ 46.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2021-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287751
关键词：
7SL RNA Adolescence Animal Model Astrocytes Ataxia Atrophic Behavioral Biological Models Birth Brain Cell physiology Cells Cerebellum Cerebrum Characteristics Childhood Chronic Clinical Clinical/Radiologic Cognitive Cognitive deficits Defect Developmental Delay Disorders Diagnosis Disease Disease Progression Electron Microscopy Endocrine Engineering Exhibits Flow Cytometry Fractionation Genetic Genetic Transcription Goals Grant Growth Hypodontia Immunohistochemistry Inherited Intellectual functioning disability Knock-in Knock-in Mouse Knock-out Knowledge Magnetic Resonance Imaging Microglia Modeling Molecular Motor Mus Mutation Myopia Neuraxis Neurodegenerative Disorders Neurologic Deficit Neurons Oligodendroglia Onset of illness Palliative Care Pathogenesis Pathogenicity Patients Phenotype Polymerase Population Protein Biosynthesis Protein Secretion RNA Polymerase III RNA Processing RNA Splicing Research Ribosomal RNA Role Sensorimotor functions Severity of illness Somatic Cell Spinal Cord Syndrome System Testing Therapeutic Time Tissues Transcript Transfer RNA U6 small nuclear RNA Untranslated RNA Variant Work base behavioral phenotyping cell type cognitive function cognitive regression disease phenotype genetic approach human disease leukodystrophy motor control mouse model mutant myelination neurobehavioral neuropathology novel public health relevance relating to nervous system therapeutic evaluation transcriptome

项目摘要

Project Summary RNA polymerase (Pol) III-related leukodystrophy is a recently identified autosomal recessive neurodegenerative disorder that causes hypomyelination with variable disease onset and severity. The disease is usually identified during childhood based on neurological deficits that include developmental delay, cognitive regression, a progressive decline in motor function and intellectual disability. Additional clinical characteristics can include myopia, hypodontia and endocrine abnormalities. An understanding of the disease mechanisms is currently lacking and progress has been limited by the absence of an animal model. Recent work has generated a lineage-specific knock-in mouse model of Pol III-related leukodystrophy that exhibits a subset of disease features found in patients and a relatively mild disease course. However, this model lacks gross motor defects and cerebellar phenotypes that are generally associated with more severe disease. Pol III-related leukodystrophy patients express mutant Pol III subunits in all somatic cells yet the disease is predominantly limited to the central nervous system. Thus, to better model the human disease, a conditional whole-body knock-in mouse was developed. This mouse model exhibits gross motor defects and a more severe disease course. The goals of this proposal are to characterize behavioral and neuropathological phenotypes of these mice and to profile Pol III transcriptional changes in neural cell populations to develop a molecular understanding of disease pathogenesis. In addition, we will test a genetic strategy for suppression of transcriptional and disease phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-related leukodystrophy and will provide a whole-body model system for testing therapeutic approaches targeting the disease.

项目总结