Our goal is to understand the basis of immune and inflammatory responses within the CNS. Immunological activation of macrophages/microglia and astrocytes leads to the production of cytokines that impact on glial and neuronal function. Cytokines have far-reaching effects in the CNS, including the initiation and regulation of immune/inflammatory responses. Macrophages/microglia and astrocytes not only produce cytokines, but also respond to them via cell surface receptors. Macrophage/microglial and astrocytic activation in general is aimed at promoting a beneficial restoration of endangered CNS elements and functions. However, excessive and sustained stimulation of these cells contributes to acute and chronic neuropathologies. Therefore, dysregulation of macrophage/microglial and astrocytic cytokine production and responsiveness may promote direct neurotoxicity, as well as disturb neural cell functions. The biological effects of cytokines are mediated by intracellular signal transduction pathways;the most common being the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway (JAK-STAT). Cytokines implicated in CNS pathology include IFN-y, IFN-p and IL-6 family members, all of which signal through the JAK-STAT pathway. A precise regulation of both the magnitude and duration of JAK and STAT activation is essential, as dysregulation of the JAK-STAT pathway has pathological implications. Suppressors of Cytokine Signaling (SOCS) proteins function to inhibit the JAK-STAT pathway. SOCS proteins are inducible by cytokines, and inhibit signaling by directly binding to cytokine receptor chains or associated JAKs to inhibit tyrosine kinase activity, thereby functioning in a negative feedback loop. There is limited information regarding the expression and function of SOCS proteins within the CNS. Our preliminary results indicate that both SOCS-1 and SOCS-3 function to attenuate expression of genes critical for immune/inflammatory responses in macrophages/microglia and astrocytes. We hypothesize that expression of SOCS-1/SOCS-3 will attenuate cytokine-induced inflammatory and immune responses by inhibiting activation of these cells, thereby exerting beneficial effects for immune-mediated CNS diseases. We will examine the ability of astrocytes, microglia and macrophages to express SOCS-1/SOCS-3 proteins in response to CNS-relevant stimuli, and elucidate the transcriptional programs underlying SOCS-1/SOCS-3 gene transcription (Aims 1 and 3). The ability of SOCS-1/SOCS-3 to modulate immunological and inflammatory responses in glial cells and macrophages will also be examined (Aims 2 and 4), using macrophage and astroglial cell lines that express siRNA against SOCS-1/SOCS-3 in an inducible manner. Our proposed studies will provide the first biological assessment of SOCS-1/SOCS-3 production and function in cells of the CNS, thereby providing the basis for future assessment of SOCS-1/SOCS-3 as attenuators of inflammatory and neurotoxic responses in the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS057563-02S1
Application #
7848397
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Bosetti, Francesca
Project Start
2007-12-15
Project End
2012-08-31
Budget Start
2009-07-20
Budget End
2012-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$81,713
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Gibson, Sara A; Benveniste, Etty N (2018) Protein Kinase CK2: An Emerging Regulator of Immunity. Trends Immunol 39:82-85
Gibson, Sara A; Yang, Wei; Yan, Zhaoqi et al. (2017) Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation. J Immunol 198:4244-4254
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Park, Keun Woo; Lin, Ching-Yi; Benveniste, Etty N et al. (2016) Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury. Exp Neurol 284:98-105
Zhao, Jiping; Yu, Hao; Liu, Yudong et al. (2016) Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 311:L868-L880
McFarland, Braden C; Marks, Margaret P; Rowse, Amber L et al. (2016) Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma. Oncotarget 7:20621-35
Rajbhandari, Rajani; McFarland, Braden C; Patel, Ashish et al. (2015) Loss of tumor suppressive microRNA-31 enhances TRADD/NF-?B signaling in glioblastoma. Oncotarget 6:17805-16

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