Our Focus and Vision
Our research seeks to understand how the central nervous system (CNS) adapts to aging, stress, and disease, and why certain CNS regions or cell populations are more vulnerable than others. We are broadly interested in the mechanisms that govern CNS resilience, with particular emphasis on neuroimmune interactions, glial biology, and intercellular communication. A major focus of our work is understanding how glial cells, especially microglia and oligodendrocyte precursor cells (OPCs), sense and respond to changes in their local environment across different physiological and pathological contexts. We investigate how these responses influence tissue homeostasis, neural function, and long-term brain outcomes, and how dysregulation of these processes contributes to neurological disease. Methodologically, we integrate molecular, cellular, and systems-level approaches, including spatially resolved multi-omics, advanced imaging, high-dimensional cytometry, genetic tools, disease models, and functional perturbation strategies. Through this interdisciplinary framework, we aim to uncover fundamental principles of CNS vulnerability and resilience and to identify new therapeutic avenues for neurological disorders.
We ask:
1. Why do specific CNS regions exhibit selective vulnerability during aging and disease?
2. How do microglia regulate CNS homeostasis in a spatiotemporal manner, and what are the context-dependent molecular cues involved?
3. How can microglial innate immune memory and state trajectory be manipulated to improve disease outcomes?
4. What are the physiological functions of OPCs beyond their role in myelination?
5. How do CNS cells communicate through specialized signaling mechanisms to regulate brain function and repair?
Projects
Microglial Kaleidoscope: microglial heterogeneity with spatiotemporal resolution
A central pillar of our research program is what we term the “microglial kaleidoscope”: a systematic effort to decipher microglial heterogeneity across CNS regions with spatiotemporal and functional resolution. Microglia continuously survey diverse microenvironments, and accumulating evidence suggests that these environments shape distinct microglial states with context-dependent functions. We aim to identify the molecular cues and signaling pathways that drive transitions between microglial states and to understand how these trajectories influence disease onset and progression. Specifically, we seek to uncover region-specific microglial states that govern local neuronal and myelin fate in a cell-non-autonomous manner. Ultimately, this work will inform strategies to steer microglial functional states toward protective phenotypes, creating opportunities for early intervention in disorders such as Alzheimer’s and Parkinson’s disease.
Once Bitten, Twice Shy: microglial innate immune memory and long-term brain outcomes
Brain fog is a widely reported long-term consequence following COVID-19 infection, while postoperative cognitive dysfunction (POCD) frequently occurs after major surgery, particularly in elderly individuals. These observations raise a fundamental question: how do transient life experiences or physiological insults become biologically embedded in the brain and lead to persistent functional alterations during aging and disease? While long-term changes in neural circuits are thought to underlie these outcomes, microglia and neuroinflammation play critical roles in shaping the brain environment over prolonged periods. As resident immune cells of the CNS that actively regulate synapses, neuronal activity, and tissue homeostasis, microglia are uniquely positioned to couple environmental experiences to long-term brain function. Traditionally, immunological memory was considered a defining feature of the adaptive immune system; however, pioneering studies have demonstrated that innate immune cells, including microglia, can also acquire long-lasting memory-like states through epigenetic and metabolic reprogramming. We investigate how early-life stress, infection, surgical trauma, or inflammation induce persistent microglial memory states, how these states interact with neural circuit remodeling, and whether maladaptive neuroimmune memory can be therapeutically reprogrammed to improve long-term brain outcomes.
CNS Butterfly Effect: from subcellular signaling to system-level brain function
b. OPCs express singular primary cilia (preliminary data).
Primary cilia are highly specialized sensory organelles that integrate extracellular signals and coordinate downstream intracellular responses. We hypothesize that primary cilia function as critical signaling interfaces that couple intercellular communication to spatially propagating changes in CNS physiology and pathology. In particular, we investigate how primary cilia enable OPCs to sense and respond to signals from neighboring cells, and how disruption of these signaling hubs reshapes cellular identity, myelin dynamics, neuronal activity, and tissue homeostasis. While OPCs have traditionally been studied as progenitors of myelinating oligodendrocytes, they may possess broader physiological functions that remain to be defined. By linking subcellular signaling architecture to tissue-level and behavioral phenotypes, this work seeks to establish a mechanistic framework for understanding how subtle perturbations in cellular signaling can drive system-wide alterations during aging and neurological disease.
The Arsenal: advance novel therapeutic strategies to combat neurological disease
A major translational goal of our research is to develop innovative therapeutic strategies that precisely modulate neuroimmune interactions across diverse neurological conditions. We integrate in silico drug discovery, bioactive compounds inspired by traditional Chinese medicine, non-invasive therapeutic approaches, and advanced nanotechnology-based delivery systems to target disease-relevant pathways in a context-dependent manner. In particular, we are interested in engineering programmable therapeutic platforms, such as DNA origami-based nanostructures, for the precise targeting and controlled modulation of microglial function within the CNS in neuroinflammatory, neurodegenerative, and neurooncological contexts. This program aims to bridge fundamental discovery with translational innovation and establish new therapeutic avenues for diseases with limited treatment options.
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