My laboratory focuses on human neurobiology, with a particular interest in how the immune system contributes to homeostasis and pathology in the central nervous system (CNS). Our understanding of the heterogeneity of human CNS cells in health and disease remains limited, and we are therefore pursuing large-scale multi-omic & spatial profiling in thousands of human brain and spinal cord samples to map how different cell subtypes interact with one another and how these interactions contribute to aging and neurodegeneration. We are thus dissecting cellular communities involved in the onset and course of human neuropathologies. Using network analyses, we are defining and validating (with gene editing screens in iPSC-derived cells) regulatory factors that play a key role in glial cell subtype’s differentiation and in the transcriptional programs that contribute to neurodegeneration. In parallel, we have developed a model of 12 subtypes of human living microglia derived from 460,000 microglial transcriptomes collected across CNS regions and diseases, and we have built a human microglial toolkit that includes RNAscope and proteomic reagents to assess these microglial subtypes, and, using in silico resources, we have identified and validated compounds which polarize microglia towards different subtypes. Thus, we are empirically characterizing the heterogeneity of the aging brain and identifying tools with which we can manipulate cell subtypes and programs to prevent diseases such as Alzheimer’s (AD) and multiple sclerosis (MS), the diseases that we focus on in the laboratory.
In addition to working on fresh, fixed, and frozen brain tissue from aged individuals, AD and MS, we have contributed to defining the genetic architecture of MS and AD, and we mechanistically dissect the functional consequences of risk-associated variants, particularly in myeloid cells such as microglia. Ongoing projects have built on this work to develop biomarkers for monitoring the onset of MS and AD as well as identifying compounds that can prevent the onset of disease. Finally, we have developed trajectories of immunosenescence to understand how the aging immune system is related to aging-related neurodegeneration.