Homeodomain Nkx2-5-dependent Negative Feedback Loop Important In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,330,245.00
Summary
Congenital heart disease (CHD) is the cause of most deaths in children in the first year of life. We have identified a genetic pathway important for both normal cardiac development and CHD that involves the cardiac transcription factor Nkx2-5. This pathway controls a transition in embryos between cardiac cell specification and expansion. We will now explore the biochemical and genetic mechanisms underlying this pathway to help us understand CHD and identify its causative genes.
The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
MicroRNA Networks That Safeguard The Functional Program Of Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,941.00
Summary
A newly discovered group of molecules termed microRNAs are thought to function as rheostats for the activity of genes. We have shown that these molecules are critical for the function of an immune cell type termed regulatory T cells. Without these cells, the immune system is unable to prevent uncontrolled and destructive inflammation. This proposal aims to utilize diverse technologies to uncover the precise molecular mechanisms by which microRNAs safeguard the function of regulatory T cells.
Chondrocyte Hypertrophy In Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$360,018.00
Summary
Whereas chondrocyte hypertrophy is a normal feature of skeletal growth, in adult chondrocytes it is associated with osteoarthritis (OA). We propose that collagen II fragments provide signals for hypertrophy in cartilage. The lack of collagen II fragments in our collagenase-resistant mouse provides a unique opportunity to address the role of collagen II fragments in driving cellular hypertrophy. We will identify bioactive collagen II fragments that represent novel targets for OA therapies
Identifying Long-range Regulatory Elements Of The Breast Cancer Susceptibility Gene, BRCA1
Funder
National Health and Medical Research Council
Funding Amount
$612,842.00
Summary
BRCA1 is a breast cancer susceptibility gene implicated in both familial and sporadic breast cancers. The mechanisms controlling BRCA1 expression are poorly understood. We will identify DNA sequences critical for regulation of the BRCA1 gene. We hypothesise that these regions are mutational hot spots conferring an increased breast cancer risk. A better understanding of the pathways responsible for promoting BRCA1-associated breast cancer will provide important diagnostic and treatment targets.
The Contribution Of Upstream Open Reading Frames To The Eukaryotic Proteome
Funder
National Health and Medical Research Council
Funding Amount
$197,911.00
Summary
This project will investigate the novel idea that genomes of complex organisms (including human) 'double-dip' with many genes containing information for more than one protein. It will also examine if these small supernumary proteins have cell regulatory functions. If proved, it would significantly alter current views on the information content of higher vertebrate genomes. An understanding of the roles of these novel protein sequences may result in the development of new drugs.
HIV infection continues to be a global problem, an effective vaccine is critical to halting its spread. For those infected there is no cure. They require life-long, expensive therapy. The proposed research looks to provide insights that will contribute to the development of an effective vaccine and to clearing the virus from infected patients by using cutting edge laboratory techniques to study patients in populations that are pathogenically informative.
Cell Therapy To Prevent And Treat Graft-versus-host Disease After Allogeneic Haematopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$260,302.00
Summary
In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation ....In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation safer.Read moreRead less