A New Paradigm For SWI/SNF Chromatin Function; The ATPase Dependent Remodeler Is A Component Of The MeCP2 Complex
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation ....DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation specific (methyl-CpG binding domain, MBD) proteins have the capacity to bind to methylated sequences and repress transcription. The mechanisms that target CpG methylation however still remain unclear. Furthermore, it is becoming increasingly evident that methyl-CpG binding proteins are not alone in silencing transcription and other epigenetic components are thought to influence transcription (namely, SWI-SNF activation complex). This grant proposal concentrates on our most recent work which demonstrates a new molecular mechanism of transcriptional repression extending the mechanism mediated by MeCP2. Our results are the first to show that the human SWI-SNF ATPase complex is a transcriptional repressor and is identified as part of the MeCP2-histone deacetylase repressor complex. This data extends the mechanistic link between DNA methylation, chromatin remodelling and transcriptional regulation. More importantly, the experimental findings could lead to a re-examination of the mechanistic basis behind MeCP2 transcriptional repression and epigenetic modification. Our findings suggest a new paradigm for SWI-SNF as a component of the MeCP2 methylation dependent silencing complex.Read moreRead less
The Distinctive Roles Of Tissue Transglutaminase Isoforms In Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$311,567.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Neuroblastoma caused by N-Myc oncogene accounts for about one third of the disease and represents a more aggressive subtype with a worse clinical outcome. This project aims to identify factors responsible for N-Myc-induced neuroblastoma initiation and factors sensitizing neuroblastoma cells to anti-cancer drugs, and to provide the basis for clinical trials of a combination therapy in children with neuroblastoma.
Targeting Histone Deacetylases For The Therapy Of Myc-induced Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$356,513.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Pancreatic cancer is the fourth leading cause of cancer death in adults. In this application, we will define how proteins called histone deacetylases promote cancer initiation and progression, and whether combination therapy with an inhibitor of the histone deacetylases and another anti-cancer agent exert efficient synergistic anti-cancer effects in animal models of neuroblastoma and pancreatic cancer.
Targeting The Histone Methyltransferase DOT1L For The Therapy Of Myc-induced Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$356,127.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Pancreatic cancer is the fourth leading cause of cancer death in adults. In this application, we will define how a protein called histone methyltransferase DOT1L promotes cancer initiation and progression, and whether inhibitors of the histone methyltransferase DOT1L exert efficient anti-cancer effects against neuroblastoma and pancreatic cancer.
A Phase II Study Of Continuous, Low-dose LBH 589 (Panobinostat) In Patients With Refractory Solid Tumors, Including CNS Tumors
Funder
National Health and Medical Research Council
Funding Amount
$811,512.00
Summary
Research done recently across three separate Australian laboratories has shown great promise with a new anti-cancer drug LBH589 used for cancers in children and young adults. We wish to start a clinical trial of LBH589 in children and young adult patients with cancer.
Targeting The Class IIa Histone Deacetylases In Metabolic Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Dysfunctional metabolism in skeletal muscle is integral in the development of metabolic diseases, such as obesity and type 2 diabetes. This project will examine proteins that alter the way genes are expressed for their role in dysfunctional metabolism in muscle. This project could uncover new therapies for the treatment of metabolic diseases.
Studying The Function And Mechanism Of Histone ADP-ribosylation; (ii) Lipo-peptide--protein Vaccine Development
Funder
National Health and Medical Research Council
Funding Amount
$496,076.00
Summary
(i) Histones, which act as DNA supports, are subject to modifications, which may be associated with disease (e.g. cancers). A better understanding of these modifications will provide access to new medicines (ii) The production of new vaccines requires new vaccine development tools. We propose to use fats to produce vaccines which can be delivered via the mouth or nose rather than by injection.
Regulation Of Macrophage Gene Expression And Function By Histone Deacetylases
Funder
National Health and Medical Research Council
Funding Amount
$35,909.00
Summary
Macrophages are white blood cells that play a major role in the development of inflammatory diseases such as rheumatoid arthritis and atherosclerosis, diseases that are a major burden to Australian society. This project aims to characterise the effects of a novel class of potential anti-inflammatory agents on macrophages. Defining how these drugs modify macrophages in disease models will allow design of therapeutics with minimal side effects.