Abstract

This project will harness the power of Drosophila genetics to complete a genome-wide analysis of the mechanisms controlling toxicity of AxD-linked mutant human GFAP to glia. New, comprehensive collections of transgenic RNAi lines will be crossed to the Drosophila model of AxD. Rigorous validation studies will confirm the identities of modifier genes. Candidate genes and pathways will then be prioritized for detailed mechanistic analysis in close collaboration with other members of the Program Project. We will also confirm and extend preliminary data we have developed implicating NO as a secreted signal that promotes neuronal death. Specifically, we will use a new expression system we have developed to test the hypothesis that glia release NO, which then activates cell death pathways in neurons through cGMP-dependent pathways. These studies are expected to significantly enhance our understanding of the mechanisms by which glia promote nervous system dysfunction in AxD specifically, and in neurological diseases more generally.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD076892-02
Application #
8929273
Study Section
Special Emphasis Panel (ZHD1-DSR-K)
Project Start
Project End
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
2
Fiscal Year
2015
Total Cost
$380,184
Indirect Cost
$37,261

  Institution

Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Wang, Liqun; Xia, Jing; Li, Jonathan et al. (2018) Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun 9:1899
Jones, Jeffrey R; Kong, Linghai; Hanna 4th, Michael G et al. (2018) Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. Cell Rep 25:947-958.e4
Hagemann, Tracy L; Powers, Berit; Mazur, Curt et al. (2018) Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease. Ann Neurol 83:27-39
Moody, Laura R; Barrett-Wilt, Gregory A; Sussman, Michael R et al. (2017) Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease. J Biol Chem 292:5814-5824
Sun, Wei; Cornwell, Adam; Li, Jiashu et al. (2017) SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions. J Neurosci 37:4493-4507
Qian, Kun; Huang, Hailong; Peterson, Andrew et al. (2017) Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo. Stem Cell Reports 8:843-855
Kjaerby, Celia; Rasmussen, Rune; Andersen, Mie et al. (2017) Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function? Neurochem Res 42:1810-1822
Lin, Ni-Hsuan; Huang, Yu-Shan; Opal, Puneet et al. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27:3980-3990
Tao, Yunlong; Zhang, Su-Chun (2016) Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell 19:573-586
Lu, Jianfeng; Zhong, Xuefei; Liu, Huisheng et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89-94

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