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Exploring the contribution of astrocytes to Huntington disease

探索星形胶质细胞对亨廷顿病的贡献

基本信息

批准号：
9324375
负责人：
Michelle Gray
金额：
$ 32.31万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324375
关键词：
Adult Affect Affective Age Animals Astrocytes Behavioral Brain Breeding CAG repeat Cells Cessation of life Clinical Cognitive Corpus striatum structure Data Disease Dominant-Negative Mutation Electrophysiology (science)Exocytosis Extracellular Space Genes Genetic Glial Fibrillary Acidic Protein Glutamate Receptor Glutamate Transporter Glutamates Goals High Pressure Liquid Chromatography Huntington Disease Huntington gene Knowledge Laboratories Lead Length Measures Mechanical Stimulation Microdialysis Motor Mus Mutate N-Methyl-D-Aspartate Receptors Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Onset of illness Pathogenesis Patients Phenotype Physiology Play Risk Role SNAP receptor Site Slice Source Symptoms Synapses Synaptic Transmission Testing Therapeutic Intervention Toxic effect base cell type clinical Diagnosis design disability disease phenotype effective therapy excitotoxicity extracellular in vivo motor deficit mouse model mutant nervous system development neuronal excitability neurotransmission novel therapeutic intervention public health relevance transmission process vesicular release voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits which progress to severe disability and death. To date there are no affective treatments for HD. The mutated huntingtin (mHTT) protein is widely expressed in neuronal and non-neuronal cells, yet neurodegeneration critically affects a few subsets of neuronal cell types in the brain. Understanding the toxicity produced by mhtt in non-neuronal cell types and the basis for this selective neurodegeneration are likely to be critical in the desin of effective therapies for the disease. The goal of this proposal is to expand our knowledge of the contribution of full length-mHTT (fl-mHTT) expressing astrocytes to neurodegeneration in HD. Astrocytes are critical to the proper function and development of the nervous system. They are involved in modulating synaptic activity and neurotransmission. Studies from our laboratory have uncovered increased SNARE-dependent glutamate release from astrocytes in culture taken from the conditional fl-mHTT expressing BACHD mouse model. This is a new found disruption caused by fl-mHTT expression in the astrocytes, which further implicates these cells in HD pathogenesis. Furthermore, we demonstrate that reducing fl-mHTT expression in astrocytes in vivo, contributes to the behavioral and neuropathological phenotypes observed in the conditional BACHD mouse model. The studies proposed here will further our understanding of astrocyte contribution to HD and determine if targeting this cell type for therapeutic intervention is worthwhile. We will use conditional genetic mouse models in these studies and propose three aims: 1) To determine if fl-mHTT expressing astrocytes contribute to HD pathogenesis by increasing glutamate levels in BACHD mice through exocytosis of glutamate; 2) To determine if expression of mutant huntingtin in astrocytes contributes to the abnormal medium spiny neuron physiology observed in BACHD mice; and 3) To determine if decreasing fl-mHTT expression in astrocytes after disease onset in BACHD mice is sufficient to alleviate HD symptoms and whether astrocyte specific expression in a new mouse model is sufficient to cause HD-like phenotypes in mice. Together these studies will help to define the role of fl-mHTT within astrocytes in HD pathogenesis, and may lead to novel therapeutic approaches for treatment of HD.