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rAAV-mediated knockdown for Huntington's disease

rAAV 介导的亨廷顿舞蹈病敲除

基本信息

批准号：
7848671
负责人：
RONALD J MANDEL
金额：
$ 2.14万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848671
关键词：
Affect Alleles Area Basal Ganglia Behavior Birth Brain CAG repeat Cell Death Cells Cessation of life Cognitive Cognitive deficits Complement Corpus striatum structure Data Defect Development Disease Disease Progression Disease model Engineering Exons Functional disorder GAG Gene Gene Transfer Genes Genetic Human Huntington Disease Inclusion Bodies Induced Mutation Inherited Knock-in Mouse Knowledge Lead Link Mediating Messenger RNA Metric Modeling Motor Mus Neurodegenerative Disorders Neurons Nuclear Inclusion Nuclear Protein Nuclear Proteins Pathology Pathway interactions Patients Proteins Recombinants Research Personnel Series Small Interfering RNA Specificity Symptoms Testing Time Toxic effect Transcript Transgenic Mice Transgenic Organisms Work adeno-associated viral vector base design disease phenotype gain of function human Huntingtin protein knock-down mouse model mutant nervous system disorder neuron loss neuropathology postnatal prevent programs protein aggregation putamen success

项目摘要

Huntington's disease (HD) is an autosomal dominant inherited progressive neurological disorder. The neuorpathological symptoms appear to be caused by progressive dysfunction and death of neostriatal neurons and/or the cortico-striatal tract. The HD gene was first described in 1993 and the gene defect was identified as an expansion of a series of CAG repeats above a threshold level in exon 1 of a gene encoding a protein called huntingtin. Subsequently, similar repeat expansions have been identified in eight other genes that are known to cause different neurological disorders when the trinucleotide expansions reach thresholds typical for each disease. These different disorders are also conceptually linked because, like HD, symptoms are caused by the dysfunction of specific neurons in the CNS. Moreover, in all CAG expansion mutation- induced disorders, the mutant protein seems to induce abnormal nuclear protein aggregations termed neuronal intranuclear inclusions. In HD, the best data seem to indicate that both a toxic gain of function and a loss of some normal function in the mutant form of huntingtin leads to neuropathology. Thus, our proposal aims to use recombinant adeno-associated viral vectors to deliver genes encoding constructs to knock-down huntingtin in striatal neurons. Long-term knock-down of striatal huntingtin will test the hypothesis that reduced huntingtin expression should limit the formation of neuronal Intranuclear inclusions in transduced neurons and thereby slow disease progression in mouse models of HD. We will use small interfering RNAs (siRNAs) to knock-down huntingtin in striatal neurons. Moreover, we propose two ways to test the hypothesis that normal huntingtin expression is beneficial.. First, we will compare the effects of huntingtin knock-down in both knock-in HD mice and transgenic HD mice. Since transgenic HD mice still express the normal amount of mouse huntingtin, our hypothesis predicts that huntingtin knock-down will be more beneficial in the transgenic mice compared to the knock-in HD mice that have only mutant huntingtin expression. Second, it is unclear whether striatal dysfunction originates in a cell autonomous fashion in striatal neurons or is caused by mutant huntingtin-induced cortico-striatal dysfunction. We will directly test this hypothesis by transducing cortical areas vs. striatal areas. We will use reduction in the amount of striatal neuronal nuclear inclusions and reversal of known transcriptional changes as our initial screen for beneficial effects followed by detailed functional analysis of motor behavior as metric of success of these strategies.

亨廷顿氏病（HD）是一种常染色体显性遗传进行性神经系统疾病。的