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Astrocytes contribution to tuberous sclerosis pathology

星形胶质细胞对结节性硬化症病理学的贡献

基本信息

批准号：
8995715
负责人：
Angelique Bordey
金额：
$ 24.98万
依托单位：
YALE UNIVERSITY
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：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8995715
关键词：
Address Alleles Alzheimer&apos s Disease Apolipoprotein E Apolipoproteins Astrocytes Autistic Disorder Axon Behavior Brain Cancer Center Cerebrospinal Fluid Cholesterol Complex Conditioned Culture Media Data Defect Development Diagnosis Disease Electroporation Exhibits FRAP1 gene Foundations Future Genetic Transcription Glial Fibrillary Acidic Protein Grant Health Human Hyperactive behavior Immunoblotting Impairment In Vitro Individual Infant Investigation Label Length Mendelian disorder Mus Mutation Neurodevelopmental Disorder Neuroglia Neurologic Neurons Pathology Patients Pattern Play Population Proteomics Role Seizures Social Behavior Symptoms TSC1 gene TSC2 gene Testing Therapeutic Time Transgenic Mice Tuberous Sclerosis Tuberous sclerosis protein complex Validation Work autism spectrum disorder axon growth base brain abnormalities cancer proteomics in utero in vivo macroglia neural circuit neuron development neuropsychological novel novel strategies postnatal premature promoter recombinase research study trait

项目摘要

DESCRIPTION (provided by applicant): The precise timing of formation and length of axonal connectivity in the developing brain is essential for proper neural circuit connectivity and function. As such, alterations in axonal connectivity are thought to contribute to neuropsychological impairments in autism spectrum disorder including monogenic disorders associated with autism such as tuberous sclerosis complex (TSC). TSC individuals express a silencing mutation in one TSC1 or TSC2 allele leading to hyperactivity of the mammalian target of rapamycin complex 1 and 40-60% of these individuals display mild to severe autistic traits and other neuropsychological problems that are independent of seizures or gross brain abnormalities. In TSC as well as other disorders associated with autism, the mechanisms leading to altered axonal connectivity remain unclear. One possible mechanism that remains unexplored is the contribution of astrocytes to abnormal axonal growth in TSC. Astrocytes are a subtype of macroglia that play a critical role in regulating neuronal development including axon elongation. Here, we thus propose to test the hypothesis that Tsc1+/- astrocytes contribute to increased axonal growth in TSC. We have two aims. The first aim proposes to assess whether Tsc1+/- astrocytes accelerate axon growth and increase axonal patterning. Using iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomics, we identified several molecules altered in Tsc1+/- astrocyte-conditioned medium, such as apolipoprotein E (apoE) that is a good candidate for controlling axon elongation. The second aim proposes to examine whether reduced apoE levels in Tsc1+/- astrocytes contributes to abnormal axon growth. To address our hypothesis, we will use purified cultures of astrocytes and neurons as well as in vivo approaches using conditional transgenic mice to delete one allele of Tsc1 selectively in astrocytes combined with in utero electroporation to label selective neuronal populations or single cortical neurons for axon tracing.