Quick Project Snapshot
The Role of Innate Phagocytosis in the Pathogenesis and Treatment of Alzheimer's Disease (for PhD only)
Emerging genetic evidence suggests that impaired removal of aggregated or fibrillar Aβ-peptides due to defects in innate phagocytosis is a major contributor to the risk of sporadic Alzheimer’s disease (AD). We found that both proinflammation and innate phagocytosis can be mediated by the P2X7 receptor in the presence or absence of its ligand extracellular ATP. In a blind pilot study we measured the phagocytic ability of fresh peripheral monocyte subsets from over 90 patients and controls recruited via the Australian Imaging Biomarker and Lifestyle Study of Aging (AIBL). Cells treated with ATP showed decreased phagocytic ability while Copaxone (CPX, also known as glatiramer acetate, a peptide polymer drug for multiple sclerosis) promoted innate phagocytosis. Significant differences of ATP and CPX altered phagocytosis were found between cognitively normal older controls and patients with mild cognitive impairment (MCI) or AD, and both were correlated with amyloid burden as assayed by Aβ amyloid-PET imaging (Gu et al, Acta Neuropathologica 2016). In this project, the candidate will further investigate the underlining biological mechanisms of these correlations through cell ageing, membrane fluidity, innate phagocytosis and inflammation. A combination treatment targeting both innate phagocytosis and inflammation will be developed in an animal model of AD and a small-scale Phase IIa pilot clinic trial for prodromal or mild/moderate AD patients, based on our novel findings. The safety and tolerance for the treatment combination (CPX which promotes innate phagocytosis and AZD9056 which inhibits P2X7 mediated proinflammation) and its therapeutic effect will be assessed during this trial. Outcome measures for Proof of Concept and Proof of Mechanism include reversal of the peripheral monocyte phagocytic deficits and changes in brain microglial activation as assessed by PET-TSPO imaging. This study will lead to better understanding of the pathogenesis of AD and a novel treatment strategy for AD.
Techniques involved include flow cytometry, microsurgery, cell culture, animal handling, fluorescent microscopy and biochemistry.
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:
- 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.
- Neurodevelopment: This lab has revealed that P2X7 mediated phagocytosis probably contributes to the early development of central nervous system by removing apoptotic neuronal cells.
- 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.
- 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 LabSearch 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)
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.