Recent studies have recognized the significant roles of astroglia (astrocytes) in central nervous system (CNS) functions including neurotransmitter uptake, water transport, control of cerebral blood flow, buffering of ions, control of neuronal synapse formation/function, sensory processing, circadian rhythms and sleep. Astroglia have also been implicated in several neurodegenerative diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (AD) and amyotrophic lateral sclerosis (ALS) and are considered to be potential targets for clinical intervention. However, how astrocytes become developmentally mature is not well understood. In parallel, previous gene expression profiling studies using microarrays have allowed the characterization and comparison of gene expression patterns for various CNS cell types including astroglia. However, microarrays, by design are limited by the bias of the probes and inability to detect uncharacterized transcripts. I addition, a detailed database of the astroglial developmental molecular changes, in particular, gene expression change and alternative transcript splicing, is currently not available. Built on our preliminary studies on employing BAC ALDH1L1 TRAP mice and next generation sequencing (NGS) technologies, we propose to generate a database resource of gene expression changes during astroglia maturation, by sequencing astrocyte translating mRNAs isolated from mouse cortex at different developmental stages in vivo. Further, the differential expression of transcripts and the extent of alternative transcripts of genes during the postnatal astrocyte development will be determined. In the secondary analysis, the gene expression changes at each time point of the development will also be analyzed to determine the enrichment of gene ontology categories, biochemical pathways and top enriched gene interaction sub- networks. The results of RNA-seq and secondary analysis will be compiled together with public annotations and integrated with other available expression data on astrocytes and made available to the neuroscience community via the web. It will be available for data mining that will facilitate functional studies of astrocytes and provide targets for clinial intervention in neurological disorders. This collaboration between a glia biologist (Dr. Yang) and a computational biologist (Dr. Iyer) is at the Neuroscience department of Tufts University with a vibrant and collaborative glia research program led by Dr. Phil Haydon and Dr. Rob Jackson.

Public Health Relevance

Astroglia, a major component of the mammalian brain including humans, has been implicated to play a role in a number of neurological disorders such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. Therefore they are considered as potential targets to develop drugs for these disorders. However, how astroglia develops is very poorly understood. In this proposal, we plan to investigate the molecular changes during astroglia development and generate a new astroglia maturation gene database for the glia research community. This database will facilitate functional studies of astrocyte and provide targets for clinical intervention in neurological disorders.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
5R03NS079805-02
Application #
8656818
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111