Microglia are resident myeloid-lineage cells in the CNS and function in the maintenance of normal tissue. Microglia can become activated and/or dysregulated during disease, and thus affect disease progression or resolution in MS. Understanding the biology of microglia is a challenge due to absence of markers and molecular microglia signatures. Recently, we identified a unique molecular microglia signature which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease. Based on this novel molecular signature we have developed unique tools to investigate microglia in EAE including 1) Identification of a unique molecular microglia signature that will be used to investigate relapsing- remitting vs. progressive EAE; 2) Generation of novel microglia and monocyte specific mAbs as tools to investigate microglia; 3) Generation of a Nanostring microglial chip; 4) Development of a new technique to culture adult microglia in vitro; 5) Generation of FCRLS-transgenic mice to study the role and function of microglia in vivo; 6) Specific Cre-dependent manipulation of gene expression in microglia and conditional ablation of microglia in EAE; 7) Identification of novel targets in resident microglia that can serve as dru targets for therapy. Based on our preliminary data we hypothesize that resident microglia have different phenotypes during different stages of CNS inflammation including phenotypes that facilitate recovery and phenotypes that perpetuate chronic inflammation. The hypothesis will be tested in the following aims:
Aim 1 : Identify the mechanism of regulation of molecular microglia signature in EAE.
Aim 2 : Investigate regulation of T cell responses by microglia during different stages in EAE.
Aim 3 : Regulation of EAE by targeting and modulation of microglia. In the revised application, we incorporate new experiments that probe the mechanisms of microglial dysfunction in EAE based on new preliminary data we have obtained making the application less descriptive. We use alternative approaches to specifically deplete resident microglia and have identified the APOE/NF?B pathway as a specific mechanism by which the homeostatic microglial signature is altered during neuroinflammation. We have removed experiments not related to the primary focus of the proposal.
The focus of this grant proposal is to characterize resident microglia and how they regulate and/or participate in CNS damage during neuroinflammation and whether CNS inflammatory disease can be treated by specifically targeting and modulating microglia. We will use new technology and approaches to understand features of microglia cells that can then be exploited to develop novel microglia-targeting therapies to treat Multiple sclerosis.
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