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Developing novel tools and methods to study microglia biology in health and disease

Dr. Butovsky’s recent studies published in JCI, 2012, Nat. Neurosci, 2014, J. Exp. Med. 2014, 2015, Nat. Neurosci, 2015, Ann. Neurol. 2015, and Immunity 2017 identified a unique microglial signature in both mice and humans and helped to elucidate the relationship of microglia to CNS disease including MS, AD, and ALS. These series of investigations lead to the identification of two major microglial subsets in health and disease and the generation of novel tools to study microglial biology such as:

1) identification of a unique molecular microglia signatures that will be used to investigate the role of microglia, modulation and immaging;
2) generation of microglia and monocyte specific mAbs;
3) development of a new technique to culture adult mouse and human microglia in vitro;
4) generation of FCRLS-transgenic mice to study the role and function of microglia;
5) identification of new role of APOE-TGFb and miR-155 signaling in regulation of microglia phenotype and function in neurodegeneration that can serve as drug targets for therapy in MS and other neurologic diseases

We continue to use and optimize these tools and methods throughout our various research projects.

Microglia in alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent form of senile dementia and affects 4.5 million Americans. In our lab, we research the role of microglia in AD. Microglia are cells within the central nervous system which we might refer to as the “big eaters”; they play an important role in the maintenance of the brain’s condition in health and disease. Through our projects, we seek to understand the different subsets of microglia within the AD brain and why they seem to be unable to efficiently clear out the amyloid plaques that build up during AD onset. We focus on certain genetic risk factors, such as apoliprotein E (APOE) and TREM2, and their involvement in microglia regulation and function. We use a combination of in vivo studies utilizing transgenic mouse models as well as human specimens with goal of finding new potential targets for treatment.

Targeting Apoe/miR155 pathway in AD microglia

We aim to restore M0-homeostatic microglia in AD mouse models by targeting Trem2-induced Apoe/miR155 pathway as well as specifically inducing Mertk pathway.

Microglia in Eye Disease

Microglia in Glaucoma
Glaucoma is a progressive blinding disease characterized by optic nerve cupping and loss of retinal ganglion cells; however, there are currently no clinically used treatments that directly promote retinal ganglion cell survival. Our lab is interested in the role of retinal neuroinflammation in glaucoma, with a particular focus on the role of microglial APOE signaling in glaucoma pathogenesis. By modulating microglial signaling in glaucoma we hope to both expand our fundamental knowledge of microglial biology and ultimately develop novel neuroprotective treatments for this common blinding disease.

Microglia in Retinitis Pigmentosa
Retinitis pigmentosa is a leading form of inherited blindness that involve a breakdown and loss of cells in the retina. We are characterizing retina microglia and how they regulate and participate in retinal damage in both animal models of retinitis pigmentosa and in eyes from human subjects in hope to better understand disease progression.

Microglia in MS

This project focuses on exploring molecular mechanisms, functions, and interactions between myeloid cell subsets, including microglia and blood monocytes, in animal models of neurodegeneration. In particular, our lab is studying the TGFbeta-APOE pathway in MS with an emphasis on examining differential effects of human APOE isoforms.

Microglia in delirium

We are investigating the mechanisms of regulating microglia in post-operative young and old subjects. By specifically targeting microglia, we aim to protect the old subjects from after-effects of general anesthesia and surgery.

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