We will investigate how the master control gene, Kruppel-like factor 1, orchestrates production of red blood cells. We will use genetic and cell biology approaches to determine exactly how this factor interprets the genome blueprint in a cell specific manner. We will also determine how mutations in KLF1 cause human diseases such as congenital dyserythropoietic anemia and hereditary persistence of fetal haemoglobin. This has implications for reactivation of HbF in adults with sickle cell disease.
Novel Transcription Factor Regulation Of Lymphatic Vascular Angiogenesis In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$831,568.00
Summary
Lymphatic vessels control tissue fluid drainage, inflammatory processes and cancer progression. We have used genetic approaches to discover an unexpected role for a family of factors (transcription factors) that regulate new lymphatic vessel formation. This project will investigate this biological function of these genes in detail in vascular formation. The project aims to generate important knowledge for vascular biology, vascular pathologies, cancer spread and future therapeutics.
Uncovering New Epigenetic-based Regulatory Mechanisms Of Gene Expression: Novel Links Between Histone Variants, RNA Function And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,053,671.00
Summary
It is estimated that greater than 90% of human genes undergo alternative RNA splicing, which can explain how protein diversity is achieved with a limited number of genes. However, how alternative splicing patterns are established remains poorly understood but is an important question given that 15-50% of human disease mutations are associated with changes to the splicing patterns of RNA. We have uncovered a new splicing mechanism, which involves changing the way DNA is packaged in a cell.
Elf5 And The Basis For Antiestrogen Resistant Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$1,181,326.00
Summary
Resistance to anti estrogen therapies causes half of breast cancer deaths. We have recently discovered (Plos Biol 2012) that the transcription factor Elf5 is intimately involved in this process. This grant will develop our understanding of the transcriptional and genomic events involving Elf5 that lead to antiestrogen resistance and metatstasis, to develop new models of antiestrogen resistance, biomarkers that predict antiestrogen resistance and new therapeutic targets and strategies that preven ....Resistance to anti estrogen therapies causes half of breast cancer deaths. We have recently discovered (Plos Biol 2012) that the transcription factor Elf5 is intimately involved in this process. This grant will develop our understanding of the transcriptional and genomic events involving Elf5 that lead to antiestrogen resistance and metatstasis, to develop new models of antiestrogen resistance, biomarkers that predict antiestrogen resistance and new therapeutic targets and strategies that prevent antiestrogen resistance.Read moreRead less
KLFs are master control genes that regulate the expression of many target genes to determine cell fate and to convert one cell fate to another. Mutations in KLFs cause human diseases. This grant will focus on the founding member of the KLF family, KLF1. We will use genomics techniques and animal models to determine how KLF1 works in normal blood cell production and in disease
Role Of ZEB/NuRD Interactions In Haematopoiesis And Lymphoid Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$810,497.00
Summary
Cancers of the blood arise from (epi)genetic changes that enable blood cells to bypass normal survival and growth checkpoints, leading to accumulation of additional mutations that drive full-scale transformation. This grant aims to understand the role of specific transcription factors (that control disease causing genes to be expressed) and how we can use a novel class of epigenetic drugs together with inhibition of these factors to selectively get rid of cancer causing blood cells in the body.
Deciphering The Overlapping Roles Of SSB1 And SSB2 In The Regulation Of Haematopoiesis And Intestinal Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$996,631.00
Summary
Our work centres on elucidating the role of two newly identified and related single-stranded DNA binding protein (Ssb1 and Ssb2) in development of blood and gut system. When both genes are deleted mice die with 8 days of knockdown due to bone marrow failure and intestinal atrophy. Our double knockout model parallels the consequences of radiation damage on blood and gut system. Toxicity to these systems is a significant hindrance in delivering anti-tumor therapy.
Role Of Common Genetic Variation Driving Single Cell Transcriptional Heterogeneity Across The Cardiomyocyte Lineage
Funder
National Health and Medical Research Council
Funding Amount
$882,698.00
Summary
In human tissues, most mature cells develop by differentiation from pluripotent stem cells. As they undergo differentiation, their transcriptional activity changes dramatically. Many of the genetic causes for these changes are unknown, which limits research in the use of stem cells for treating and modelling disease. This proposal addresses this problem with cardiac muscle cell differentiation by utilising recent developments in biotechnology that enables individual cells to be sequenced.
Understanding The Contribution Of SRNAs To Antibiotic Resistance In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$587,424.00
Summary
Golden Staph is a major problem in Australian hospitals. This project will use cutting edge technology to investigate how Golden Staph responds to and resists antibiotics used to treat human infections, leading to new strategies for the prevention and treatment of antibiotic resistant bacteria.
Co-operation Between GATA2 Mutation Or Expression And RAS Signalling In AML
Funder
National Health and Medical Research Council
Funding Amount
$860,601.00
Summary
We have identified a gene GATA2 which, when mutated, can lead to leukaemia (blood cancer). We will collect samples worldwide from families and individuals that carry GATA2 mutations and have developed leukaemia, and will screen for other genetic changes that contribute to leukaemia. We have also identified a novel group of patients who have a low GATA2 activity and who also have mutations in the RAS gene, a known contributor to leukaemia. We will determine how these cooperate to cause leukaemia.