One of the major players in innate immune system is neutrophil which is the most abundant cell type among circulating white blood cells and constitutes the first line of host defense against invading bacteria and other pathogens. The long-term goal of our research is to elucidate the molecular mechanisms that control various neutrophil functions. Our research focuses on:
1) Signal pathways mediating neutrophil directional movement
Neutrophils migrate toward sites of infection or inflammation by responding to gradients of chemoattractants, a process known as chemotaxis. Neutrophil chemotaxis is mediated by G-protein coupled receptors and downstream chemotactic signal transduction pathways. The objective of this research is to identify and characterize biochemical events that mediate the directed neutrophil movement in response to a gradient of chemoattractant.
2) Molecular mechanism of neutrophil spontaneous cell death
Neutrophils are terminally differentiated cells and normally have a very short life-span (6-7 hours in blood and 1-4 days in tissue). They readily undergo spontaneous programmed cell death (apoptosis) and this death program needs to be well controlled to maintain the normal neutrophil count. Accelerated neutrophil death leads to a decrease of neutrophil counts (neutropenia), while delayed neutrophil death elevates neutrophil counts (neutrophilia). Impaired clearance of neutrophils in tissues causes unwanted and exaggerated inflammation. The long-term goal of this project is to elucidate the molecular basis of this finely regulated death program.
3) Neutrophil homeostasis under normal and inflammatory conditions
Neutrophils in the bone marrow and circulation release various factors that can modulate hematopoiesis and myelopoiesis. Thus neutrophils may be able to create, maintain and regulate their own homeostasis in a feedback manner. We are currently exploring the role of ROS and proteases in infection-induced myelopoiesis. We are also interested in the molecular and cellular mechanisms that govern the release (mobilization) of neutrophils from the bone marrow during the course of inflammation.
4) Modulating neutrophil function in bacterial pneumonia
Chemo- and radiotherapy are extensively used to treat various hematological malignancies and solid tumors. Neutropenia and related infection are the most important dose limiting toxicities of these anti-cancer treatments, impacting on quality of life and clinical outcomes, with the potential to cause death. Neutropenia-related pneumonias are involved in 40% infection at a site other than blood alone, and usually treated with broad-spectrum antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) therapy. However, not all patients respond to antibiotic treatment and G-CSF therapy. In addition, G-CSF treatment is often associated with side-effects such as bone pain, headache, fatigue, nausea, and higher risk of getting leukemia. The long-term goal of this project is to explore another strategy for treating/preventing neutropenia-related pneumonia - via enhancing neutrophil functions (e.g. recruitment, survival, and bacteria killing) in neutropenic patients.
5) Improving neutrophil performance in granulocyte transfusion
Neutrophil transfusion has been commonly utilized as a therapeutic approach for the treatment of life-threatening bacterial and fungal infections in severe neutropenic patients. However, its clinical outcome is often hampered by short ex vivo shelf life and rapid in vivo death, inefficiency of recruitment to sites of inflammation, and poor pathogen killing capability of transplanted neutrophils. The ultimate goal of this research is to identify and characterize cellular and molecular events that can improve neutrophil performance during transfusion.
6) Novel inhibitors/modulators of PtdIns(3,4,5)P3 signaling
PtdIns(3,4,5)P3 exerts its function by mediating protein translocation via binding to their pleckstrin homolog (PH)-domains. A subset of PH-domains, including those in Btk, Protein kinase B (PKB)/Akt, PLC-y, Gab1, PDK1 and Grp1, drive membrane translocation of their host proteins through specific, high-affinity recognition of PtdIns(3,4,5)P3. This membrane translocation is crucial for these proteins to fulfill their functions in PtdIns(3,4,5)P3 mediated cellular processes such as cell survival, proliferation, growth, differentiation, polarization, chemotaxis, cytoskeletal rearrangement, and membrane trafficking. We recently conducted a high throughput screening for modulators of Akt-PH domain plasma membrane translocation. In this study, we discovered a novel mechanism for modulating PtdIns(3,4,5)P3 signaling under physiological condition.
Pathways and Methods
Currently, we are particularly interested in signaling pathways mediated by inositol phospholipid PtdIns(3,4,5)P3, inositol phosphates (e.g. InsP4 and InsP7), and reactive oxygen species (ROS). We utilize a wide variety of approaches ranging from basic molecular and cell biology methods to high throughput chemical genetic screening and animal inflammation models to dissect these pathways.