Research Program

Our research focuses on the role of inflammation and microglial reactivity in accelerating neurodegeneration. As the immune cells of the brain, microglia survey the brain for signs of injury and disease, and dynamically respond through extensive transcriptional and proteomic remodeling. Our lab seeks to understand how microglia remodel their cell-surface proteome (or surfaceome) in the Alzheimer's disease microenvironment. We believe that the cell-surface is the compartment best suited to deciphering extracellular signals and encoding neuroprotective and neurotoxic signals. By dissecting the surfaceome changes in Alzheimer's disease, our goal is to harness the neuroprotective programs while silencing the neurotoxic signals, thereby unlocking potential therapeutic avenues. 

Ongoing Projects

Elucidating the Glial Surfaceome

Our lab uses cell-surface capture mass spectrometry to interrogate the surfaceome of glia in neurodegeneration. We use iPSC models and disease-relevant perturbations to understand this dynamic remodeling process. Although microglia have to-date been our primary focus, we are eager to apply these techniques to other glial populations, including astrocytes. 

Interrogating Proteoglycans in Glial Reactivity

Our microglia surfaceome profiling demonstrates that amyloid pathology robustly upregulates cell-surface heparan sulfate proteoglycans (HSPGs). The role of HSPGs in microglia are unexplored. We find that microglial HSPGs drives a toxic cellular program that accelerates neurodegeneration in animal models of Alzheimer's. We are delving into the molecular and cellular mechanisms that mediate this interaction and aim to understand the interaction of β-amyloid, tau, heparan sulfate, and microglia. 

Engineering Antibodies to Modulate Glial Function

Antibody-based degraders are a novel technology that enables targeted degradation of cell-surface proteins. These bi-specific antibodies engage a target protein of interest with one arm while simultaneously highjacking a nearby cell-surface receptor with the other arm to shuttle the POI to the lysosome for degradation. We are leveraging this technology to degrade critical microglia cell-surface targets to enable fine-tuned modulation of microglia function and activity. 

Building Biosensors to Detect Inflammation in the Brain

Antibodies that recognize self CNS antigens can lead to a class of disorders called autoimmune encephalitides. In these inflammatory diseases, the autoantibodies can damage neuronal and glial function resulting in a wide range of neurological symptoms. The diagnosis of autoimmune encephalitidies remains a clinical challenge. We are building a panel of biosensors to enable the rapid and robust detection of pathologic autoantibodies to diagnosis these diseases. Our long term goal is to deliver accurate and rapid clinical tests that immediately inform clinician decision making ultimately improving outcomes for patients.