Diabetic Complications

Hons & PhD Programs and Projects

Program 1 - Understanding the MeCP2-associated regulatory complex in disease

Characterizing the MeCP2 corepressor associated SWI/SNF complex. what are the biophysical properties of MeCP2 in the brain? What is the significance of the complex in mental health fragile X syndrome)?

Alterations in the controls of DNA methylation and histone deacetylation play a profound role in human disease. We are interested in examining epigenetic events such as DNA methylation, histone modification and the determinants involved on chromatin to further our understanding of endogenous gene transcription. These studies are now challenging the way we view gene regulation beyond our simple understanding of "textbook" operations. Our desire to dissect the molecular details allows us to determine the roles of transcriptional regulators and provide us with a greater understanding of how they are involved in transcriptional regulation.

Program 1 - Role of MeCP2 in disease

Program 1 - Epigenetic model of transcriptional regulation

Program 1 Picture 2 Epigenetic model of transcriptional regulation

Program 2 - Improving molecular targeting and treatments for cancer gene therapy

This Hons and PhD Program will investigate the effect of HDACi on radiation-induced DSB repair in transcriptionally active or inactive euchromatin and constitutive heterochromatin analyses of γH2AX accumulation and hyperacetylation of histone H3 using chromatin immunoprecipitation (ChIP). The candidate will investigate pre-treatment with low concentration of HDACi before irradiation, results in classic hallmarks such as histone hyperacetylation and the stable accumulation of γH2AX that is more pronounced in euchromatic alleles than heterochromatic areas of the genome. At this exciting stage of gene therapy, our combined results suggest that the inhibition of HDACs can potentiate therapy by a mechanism that renders DNA more accessible to treatments by histone hyperacetylation in the absence of cytostasis, apoptosis and/or growth arrest in mammalian cells.

Program 3 - Identification of new regulatory mechanism of transcriptional repression in response to cancer chemotherapy

The central focus of this project is to take the teams latest findings on transcriptional repression to the next logical step and further extend the mechanism.

The general focus of this project is to investigate the mechanisms by which specific MBD1 regulatory complexes serve to integrate and repress gene in models of cancer. Specifically, the project will define the functional roles of specific components of the co-repressor complexes in gene repression events and characterise the link to cancer-associated loci such as the multidrug resistance gene (MDR1) using genetic and genomic approaches.

The project is aimed to examine the controversial point of MBD1 repression independent of direct DNA methylation.

Program 4 - Epigenetic memory in diabetes and metabolic syndrome

The role of the histone code hypothesis on hyperglycemic memory

Program 4 will investigate the epigenetic pathways that act as a bridge linking hyperglycaemia to the central molecular and cellular events, which lead to vascular injury in diabetes. We have identified that in the context of a hyperglycaemic milieu, transcriptional competence is directly linked with epigenetic changes. These findings present a new paradigm for histone methyltransferase function and epigenetic modification that is relevant to our understanding of the transcriptional response to glucose. Finally, these findings will provide new targets for generating end-organ protective agents for the common and devastating clinical problems of diabetic vascular complications.

Program 5 - Heart disease, stem cells and Epigentics

The role of epigenetic factors on transcriptional regulation in the failing heart.

Defining the impact of the foetal gene-expression program during the differentiation of stem cell-derived heart cells.

The work conducted in this project is aimed at reducing death and disability arising from heart disease in the community. Stem cells have the unique capacity for self-renewal and differentiation into specialised cell types. This project will use stem cell cultures to understand how the healthy heart develops and hence how heart problems can arise when development goes awry. We will look at important developmental genes and determine how they are controlled as the heart forms from embryonic, to foetal, to neonatal-like stages.

Program 6 - Mechanisms of genetic changes in imprinting disorders

Elucidating the mechanism(s) resulting in loss of imprinting in patients with epigenetic defects by analysing key trans-acting regulatory factors involved in the maintenance of imprinting during early foetal development.

Evaluating if biochemical modification of core histones may represent an alternative and/or complementary mechanism to methylation defects in patients with imprinting disorders. This project will give new insight into the mechanisms of imprinting disorders including cancer. Furthermore, recent studies indicate that the use of assisted reproductive technology can affect the epigenetic cycle of imprinting and result in BWS and SRS by a mechanism that is still unidentified. The outcome of the research will therefore highlight our understanding of the epigenetic risk of assisted reproductive technology.

Program 7 - Genome wide approaches to the study of gene-environment interactions and chromatin modifications

Development of computational tools that integrate genome-wide data sets for proximal and distal transcription binding sites and histone modification mapping.

Development of ChIP approaches and strategies to the broad application of determining epigenomic signatures in models of human health and disease.

Development of epigenomic protocols and strategies for low cell numbers from clinical isolates.

Contact for further project details

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Email Associate Professor Assam El-Osta

Ph: + 61 3 8532 1389 Fax: +61 3 8532 1100
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