Plasma membrane dynamics and signaling
Given that the cell membranes are the first defenders against external (sometimes even internal) stress, in theory, perturbations that may disrupt any type of cell membrane function should activate a multifactorial defense mechanism. We are studying how plasma membrane (PM) damage/repair and lipid mobilization happen and further affect the immune system. We also explore how this signaling evolves during system development.
For PM repair, now we know ESCRT- III complex can repair the damaged PM by membrane remodeling, in many physiological settings. The broken PM fractions can be shed off. Therefore, cells can tolerate a limited level of PM damage and survive for a long time if ESCRT-III repairing capacity is not overwhelmed. As a result, ESCRT-mediated plasma membrane repair can bring cell back from the edge of death or preserve cell survival when pore-forming activity is sufficiently low (“sub-lethal”).
The sub-lethal PM damage itself can be recognized and generate signals that result in the elaboration of secreted mediators, such as chemokines and cytokines. S660 p-PKCs sense the pore-forming damage by detecting the local Ca2+ influx, functioning as receptors to the transient plasma membrane integrity loss, leading to the downstream innate immune response (referred as, plasma membrane integrity signaling, PMI). The gene expression signature upon sub-lethal plasma membrane damage (that includes these chemokines) depends on the antagonization/delay in cell lysis affected by ESCRT-III. The roles of this cellular response for peritonitis, solid tumors, cross-priming, and kidney transplantations are also implicated.
Moving forward, we will firstly hunt for more innate immune-sensing mechanisms for PM integrity loss. We proposed to test a promising ion channel candidate that is very likely to be one of the sensors for PM damage. We have also planned an elegant cell culture system to perform both siRNA and sgRNA screens to search for the PM damage sensors genome-wide. Next, we will use both animal models and human specimens to test the roles of the chemokines/cytokines secreted by these “survivors” in tumorigenesis, metastasis, and beyond. Third, we will try to eliminate the “survivors” directly by suppressing the ESCRT- III repair action.
Tumor cell death re-programmer
Tumor cell death probing
Macrophage responses to the innate immune activation pattern
With multiple pattern recognition receptors, macrophages can sense a variety of innate activation patterns. These patterns can come from bacteria, fungi, and virus, they can also come from tumors, especially dying tumors. We study how macrophages respond to various innate immune stimuli. We focus on two questions, how do the macrophage respond (molecular mechanism) and why do the macrophage respond so (pathological significance).
Machine learning-based AI technology
We are embracing the most updated Convolutional Neural Network technology to train AI models for imaging processing, sequence analysis and target discovery, and cellular function predictions. We have already successfully trained models named LANCE and D-MAINS for cell death, proliferation, and senescence predictions, using grayscale and label-free approaches. More exciting models tailored for other biomedical science are always on the way!
More to explore...