Neuronal injury and degeneration are accompanied by inflammatory responses from the innate immune system. Central nervous system tissues have highly specialized innate immune responses mediated primarily by microglia, the resident macrophage population. Microglia invade the CNS early in embryonic development and are a highly specialized cell of myeloid origin with unique features and functions. One of those unique aspects of microglia behavior is that are normally quiescent, expressing few markers associated with other specialized macrophage behaviors. Like their macrophage cousins however, microglia can respond to changes in the CNS environment by adopting a variety of behaviors. When microglia respond to changes in their environment, they can perform functions associated with """"""""classical"""""""" macrophage activation that evolved as effective responses to bacterial and viral pathogens as well as those involved in quelling an inflammatory response or participating in the process of tissue repair. Currently, there is debate regarding which microglia functions dominate during acute or chronic injuries and no clear method of experimentally inducing microglia to adopt a specific set of behaviors. We have identified p53 as a transcriptional regulator that promotes behaviors associated with classical activation in microglia while p53 deficiency yields gene expression patterns associated with anti-inflammatory and tissue repair functions in microglia. One mechanism by which p53 influences microglia behavior was identified as negative regulation of a second transcription factor, c-Maf. The c-Maf transcription factor is a known regulator of both lymphocyte and myeloid cell differentiation, generally observed to promote the anti-inflammatory/tissue repair arm of both the innate and adaptive immune system. This proposal will further explore these discoveries by first demonstrating that the function of c-Maf in macrophages is recapitulated in microglia, second identifying the molecular mechanisms by which p53 influences c-Maf expression and third determining if p53 modulates microglia behaviors in vivo using the Cre/lox system to inactivate p53 in a time and cell type specific fashion.

Public Health Relevance

A wide variety of nervous system disease and injury states are associated with a robust inflammatory response. Currently there is no clear understanding of the molecules that regulate whether the cells responsible for this inflammatory response will behave in a manner that helps protect nervous system tissue or exacerbates the injury process. This proposal aims to study a molecular pathway that regulates inflammatory behavior outside of the nervous system to determine if it could be harnessed as a method of maximizing recovery or preventing further degeneration in a variety of diseases including stroke, Alzheimer's disease and vascular dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073848-02
Application #
8313901
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Wong, May
Project Start
2011-09-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$326,140
Indirect Cost
$115,046
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Su, Wei; Aloi, Macarena S; Garden, Gwenn A (2016) MicroRNAs mediating CNS inflammation: Small regulators with powerful potential. Brain Behav Immun 52:1-8
Garden, Gwenn A; Campbell, Brian M (2016) Glial biomarkers in human central nervous system disease. Glia 64:1755-71
Su, Wei; Kang, John; Sopher, Bryce et al. (2016) Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia. J Neurochem 136 Suppl 1:49-62
Aloi, Macarena S; Su, Wei; Garden, Gwenn A (2015) The p53 Transcriptional Network Influences Microglia Behavior and Neuroinflammation. Crit Rev Immunol 35:401-15
Jebelli, Joseph; Su, Wei; Hopkins, Stephanie et al. (2015) Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity? Ann N Y Acad Sci 1351:1-10
Su, Wei; Hopkins, Stephanie; Nesser, Nicole K et al. (2014) The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol 192:358-66
Garden, Gwenn A (2013) Epigenetics and the modulation of neuroinflammation. Neurotherapeutics 10:782-8
Jayadev, Suman; Case, Amanda; Alajajian, Betty et al. (2013) Presenilin 2 influences miR146 level and activity in microglia. J Neurochem 127:592-9
Jebelli, Joseph D; Hooper, Claudie; Garden, Gwenn A et al. (2012) Emerging roles of p53 in glial cell function in health and disease. Glia 60:515-25
Garden, Gwenn A; La Spada, Albert R (2012) Intercellular (mis)communication in neurodegenerative disease. Neuron 73:886-901

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