The Fan lab investigates the metabolic underpinnings of cell function and fate, particularly in innate immune cells. We integrate systems-level approaches with biochemical, genetic, and computational tools.
Current projects focus on the metabolic reprogramming in macrophages and neutrophils during immune response. The long-term goal is to define the role of metabolic dysregulation in immune cell dysfunction in disease and develop metabolic interventions to modulate immunity. More broadly, we seek a mechanistic understanding of how metabolic change affects cell function, signal, physiology, and survival, and how metabolism is dynamically regulated in response to stimulation and environmental perturbations in a variety of biological contexts through many collaborations.
Dynamic metabolic reprogramming in macrophages
In response to different environmental cues, macrophages develop specific phenotypes and cellular functions. The ability to appropriately assume different phenotypical states is critical for immune function. We are interested in understanding (1) how macrophage metabolism is dynamically regulated during phenotypical switches as cells respond to specific signals (2) the mechanisms driving this metabolic remodeling and (3) how altered metabolism orchestrates immune function and inflammatory state.
The lab leverages an integrated framework to examine the temporal structure of metabolic remodeling during macrophage response and elucidate metabolism–function connections. First, we use multi-omics analyses to systematically characterize what significant metabolic alterations occur during a course of immune response. This approach reveals waves of metabolic changes clustered by pathways that are associated with the sequence of functional transitions. We next apply isotopic tracing approaches to quantify how metabolic fluxes through these pathways change during immune response and identify pivotal metabolic “regulation points” (i.e., key reactions). We then perturb the key reactions genetically or biochemically to examine how the remodeling of these pathways impacts immune function. Finally, we investigate the molecular mechanisms that regulate the identified “regulation points” and the molecular mechanisms allowing the specific metabolic activity to influence immune functions.
The metabolic underpinning of neutrophil physiology
Neutrophils are the most abundant leukocytes at the frontline of innate immunity, but the metabolism of neutrophils remains a critical knowledge gap, especially compared to other immune cells. Using approaches similar to those described above for macrophages, we characterize the metabolic remodeling upon neutrophil activation by various stimuli and investigate the mechanisms through which this remodeling powers neutrophil functions. Our studies demonstrate neutrophils have remarkable flexibility in both the utilization of metabolic sources and their metabolic fates, which is essential for their role as the first responders in innate immunity. We further seek to understand the mechanisms enabling such metabolic flexibility. Furthermore, we combine genetic approaches together with quantitively characterization of metabolism to identify metabolic activities that are important for neutrophil differentiation and neutrophil fate.
Metabolic response to specific microenvironment
The environment plays an important role in shaping cellular metabolism. The ability of cells to adapt to fluctuations of nutrients and oxygen level or other metabolic stress in the microenvironment is critical for proper cellular function and survival. In collaboration with various groups, we work to elucidate the specific metabolic response and metabolic adaptation to several physiologically relevant perturbations in the microenvironment, including deprivations of specific nutrients, reactive oxygen species and reactive nitrogen species induced stress, and hypoxia. We further seek to understand the biological consequences of such metabolic rewiring induced by these specific environmental factors. A new direction is to understand the metabolic interactions among different cell types within the same microenvironment.