Dissection of Microglial State Biology in Brain Repair

Introduction

Microglia, the macrophages of the brain, are critical regulators of many neurobiological functions and implicated by human genetics in several central nervous system diseases. Recent studies have revealed that microglia can adopt distinct co-existing subtypes, termed 'states'. Microglial states appear especially in the context of damage, disease, or repair, and understanding these states may lead to the ability to precisely modulate neuroinflammation.

Knowledge Gap

However, due to a lack of datasets and tools, the dynamics and functions of these microglial states are unknown, representing a poorly explored frontier of neuroscience.

Core Goal

The core goal of this proposal is to understand the kinetics and biological roles of microglial states. Using focal brain repair in the mouse as a model system, I will address this knowledge gap with three synergistic objectives:

1. Dynamics of Microglial States
   How do microglial states change in space and time? To answer this, I will unravel the dynamics of microglial states by generating a spatiotemporal atlas of gene expression at the single-cell level, from injury to full repair.

2. Emergence and Functions of Microglial States
   How do specific microglial states emerge and what are their functions? I will address this question by focusing on one state that interacts with the peripheral immune system and appears to be triggered by a particular cytokine.

3. Molecular Tools Development
   I will build novel molecular tools to genetically access and specifically arrest any microglial state. This will enable me to investigate their impact on remyelination and uncover the biological mechanisms by which microglial states orchestrate brain repair.

Expected Outcomes

Together, this work will comprehensively dissect the biology of microglial states in brain repair and provide the enabling technologies to do the same in other contexts, from development to disease. It will open up microglial states to experimentation, resulting in a step change in our understanding of this important brain cell type.