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Project

The Role of Myeloid ATF3 in Neuroprotection following SCI

Funder: Craig H Neilsen Foundation

Funding period
USD 600 K
Funding amount
Abstract
Spinal cord injury (SCI) is a progressive disease. Secondary damage following SCI continues over weeks or months, and is characterized by an incompletely-understood inflammatory response mediated by resident and infiltrating immune cells. Activating Transcription Factor 3 (ATF3) induction has been shown to attenuate pro-inflammatory cytokine in immune cells epigenetically via remodelling chromatin accessibility. Two FDA-approved drugs, tamoxifen (TAM) and dimethyl fumarate (DMF) induce ATF3 in macrophages when activated, and this activation attenuates inflammatory cytokine production (preliminary data). The overall objective is to investigate the regulation and roles of ATF3 in neuroprotection conferred by TAM and DMF. We will use genetic and pharmacological interventions, behavioural and histological analyses, and bioinformatic methods to meet the following specific aims:
Aim 1. To determine the signaling pathways upstream of ATF3 induction by TAM and DMF. We will use activators and inhibitors of TAM and DMF-binding proteins to determine how they initiate ATF3 expression in vitro.
Aim 2. To determine the role of ATF3 in neuroprotection in vivo following SCI. We will use a CX3CR1-Cre mouse line crossed with an ATF3 floxed line to remove ATF3 from resident microglia and circulating macrophages. This will determine the effects of ATF3 deletion on neuroprotection following TAM/DMF treatment in mice with spinal contusions.
Aim 3. To determine the epigenetic and downstream effects of ATF3 induction in myeloid cells by TAM/DMF. We will use ATAC-seq to identify open chromatin (including enhancers) in FACS-purified macrophages and microglia from animals with SCI (ATF3 wild-type or ATF3-null), and SCI plus TAM/DMF. We will also carry out single-cell RNA-seq on macrophages and microglia isolated from the same groups to determine the effect of TAM/DMF-induced ATF3 on the microglial transcriptome. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Genetics

  • RCDC

    Neurodegenerative

  • HRCS HC

    Inflammatory and Immune System

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science