Supervisor View Full Details

• genetics, genomics and molecular biology
• cell and developmental biology/regenerative medicine
• cancer/oncology

• Medicine
• Surgery
• Pathology

• Nephrology
• Oncology
• Radiology

Centrosome abnormalities and amplification are common characteristics of tumour cells. Aneuploidy and chromosomal instability are highly correlated with the appearance of multiple centrosomes. Supernumerary centrosomes can cause mitotic abnormalities, such as the formation of multipolar spindles, potentially giving rise to abnormal chromosome segregation. Normally, centrosome amplification is tightly regulated during the cell cycle. Previous work from our group has demonstrated that DNA damage leads to centrosome amplification. How this happens in tumourigenesis is not well understood. Centrosome defects are also seen in patients with primary microcephaly. We are exploring how mutations in microcephaly genes disrupt the normal controls on centrosome duplication.

Centrosomes also provide the structural basis for primary cilia- small, antenna-like structures that are found on the surface on most cell types. Primary cilia direct cellular responses to chemical and mechanical signals. Defects in ciliation cause a number of developmental disorders that particularly affect organs that respond to fluid flows, including the kidney, eye, liver, brain and skeleton, collectively termed the ciliopathies. Mechanisms that link centrosome mutations to the ciliopathies remain to be explored in detail, as do potential links between ciliopathies and microcephaly.

Our laboratory uses cell biology and reverse genetics to explore how centrosomes and primary cilia are involved in human disease mechanisms. Projects of potential interest for clinican PhDs include:

1. Analysis of centrosome amplification in cell lines from primary microcephaly or ciliopathy patients. Reverse genetics using genome editing will be used to ablate or modify known centrosomal genes in cultured cells from patients with mutations in known microcephaly or ciliopathy genes. Detailed phenotypic analysis will indicate the genetic interactions that impact on centrosome and ciliary behaviour.
2. Generation of cell models for ciliopathy mutations. Using genome editing approaches, genes that we have identified as controlling ciliogenesis will be mutated in kidney or retinal cell lines and the impact on cell behaviour analysed in detail.
3. Characterisation of the impact of ciliopathy/ microcephaly mutations on centrosome dynamics. Novel monoclonal antibodies (already generated in-house) are to be optimized and tested in patient samples to examine how centrosomes are affected.
4. Candidate ciliopathy gene examination by genome editing. Candidate genes identified in clinical genetics projects will be ablated by genome editing in cultured cells and the phenotypic outcomes used to suggest mechanisms of disease.