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Investigation of P2X7 mediated phagocytosis - potential therapeutic target for cancer treatment

The P2X7 receptor was originally recognized as an ion channel for influx of Ca2+, Mg2+ and efflux of K+. Following its activation by extracellular ATP, it triggers a number of downstream pro-inflammatory responses including IL-1β, IL-18 and formation of inflammasome. Prolonged exposure to ATP (over 30 seconds) opens large pores on the cell membrane and eventually leads to apoptotic death of cells. Recent discoveries from Dr. Ben Gu’s group have demonstrated that P2X7 is also a scavenger receptor in the absence of ATP, while ATP normally dissociates P2X7 from its cytoskeletal attachment with nonmuscle myosin heavy chain IIA (also known as myosin 9) and inhibits P2X7 mediated phagocytosis. Therefore, it is clear that P2X7 has a dual functional mode: an ion channel to form pores triggering pro-inflammatory responses in the presence of ATP, and a scavenger receptor to clear apoptotic cells and cell debris in the absence of ATP.  Interestingly, the cancer cell-expressed P2X7 has been found in a non-functional conformation, rending them unable to form apoptotic pores, which prevent cancer cells from undergoing programmed cell death. Moreover, non-functional P2X7 keep tumor cells highly phagocytic even in the presence of ATP. A specific antibody against non-functional P2X7 receptors, which was found to recognize tumor cells from solid tumors, has become an unique biomarker and therapeutic reagent for various solid tumors. Its therapeutic values are currently explored clinically by the Biosceptre Pty Ltd (Cambridge, UK). In this study, we will characterize the non-functional P2X7 on the surface of tumor cells and further investigate whether and how the uncontrolled P2X7-mediated phagocytosis contributes to the uncontrolled proliferation of tumor cells. Different strategies will be used to search for inhibitors for P2X7 mediated phagocytosis.  The outcomes will lead to better understanding of oncogenesis and a possible novel treatment for solid tumor.

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HEAD OF LAB
Dr Ben Gu

Innate Phagocytosis Laboratory

The Innate Phagocytosis Laboratory led by Dr. Ben J. Gu and Prof. James S. Wiley has great interests in discovering the role of innate phagocytosis in neurodegeneration, neurodevelopment, infection and cancer. This Lab has a long history of studies on the P2X7 receptor, an ion channel activated by ATP.  They discovered the non-functional P2X7 and identified a number of genetic variations affecting P2X7 pore formation and pro-inflammatory responses. Recently they have found that P2X7 is in fact a scavenger receptor in the absence of ATP or serum. Further study of P2X7 mediated innate phagocytosis opens a new research field for its role in broad biological aspects, including:

  1. Neurodegeneration: This lab explores genetic, cell biological and animal studies to identify a common mechanism underlying a number of neurological disorders including Alzheimer’s disease, age-related macular degeneration and multiple sclerosis.
  2. Neurodevelopment: This lab has revealed that P2X7 mediated phagocytosis probably contributes to the early development of central nervous system by removing apoptotic neuronal cells.
  3. Infection: Innate immunity can be promoted by neutralizing certain glycoprotein in serum or by compounds promoting innate phagocytosis. This lab is currently developing a rabbit model of bacteraemia/sepsis.
  4. Cancer:   The non-functional P2X7 is found to be expressed on the surface of various tumor cells, but not on normal cells. The antibody against this non-functional P2X7 receptor  is currently undergoing a clinical trial for basal cell carcinoma conducted by Biosceptre Pty Ltd. This lab has great interests in investigating the biological nature of non-functional P2X7, P2X7 mediated phagocytosis and oncogenesis.

All Projects by this Lab

Search the P2X7 related biomarkers for Alzheimer’s diseaseThe nature of the P2X4 receptorThe role of P2X7 in a mouse model of oligodendrocyte apoptosisInvestigation of P2X7 mediated phagocytosis - potential therapeutic target for cancer treatmentIdentify the transcriptional regulatory factors of the P2X7 receptorHow does the brain remove the excess number of neurons during development and agingIdentification of serum glycoproteins altering innate immunityDo circulating microvesicles from patients with multiple sclerosis (MS) disrupt the blood-brain barrier (BBB)? (For Honors and MBiomedSc)The Role of Innate Phagocytosis in the Pathogenesis and Treatment of Alzheimer's Disease (for PhD only)

Epilepsy

The Florey's Epilepsy division is a world-leading centre for epilepsy research. The division has major groups at both the Florey’s Austin and Parkville campus. The group studies mechanisms that cause epilepsy from the level of cells to the function of the whole brain. We use technologies including advanced MRI and cutting edge cellular physiology techniques to allow us to understand genetic and acquired mechanisms that give rise to epilepsy. Together with our colleagues from The University of Melbourne and across Australia we are working towards finding a cure for epilepsy.

All Labs that operate in this Division

Epilepsy Cognition LaboratoryEpilepsy Neuroinformatics LaboratoryImaging and EpilepsyInnate Phagocytosis LaboratoryIon Channels and Human Diseases LaboratoryNeural Networks LaboratoryNeurophysiology of Excitable Networks LaboratoryPsychology and Experimental NeurophysiologySleep and CognitionTraumatic Brain Injury Laboratory