EPIGENETIC REPROGRAMMING OF MALIGNANT BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$863,268.00
Summary
Poorly differentiated breast cancers are aggressive tumors, frequently resistant to chemotherapy and associated with high morbidity. Herein we propose the engineering of more selective therapeutic agents able to target the genes involved in cancer initiation and resistance to treatment. We aim to correct and reprogram the cancer cell genome in state that is similar to normal, not tumorigenic cells. This work will generate novel forms of treatment for cancers that are presently not curable.
Retromer directs membrane protein trafficking within the endosome. The exposure of proteins to the extracellular environment is dependent on how the travel through the various regions of the cell. The work will lead to a richer understanding of how this process is regulated by protein complexes. These complexes act within cells to drive the formation of membrane transport tubules containing cargo molecules.
Making muscle: molecular dissection of membrane domain formation. For a muscle to contract efficiently in response to an electrical signal it requires the formation of an extensive system of hollow membranous tubules through which the signal can be propagated. This proposal addresses the molecular mechanisms involved in the formation of this tubule system in skeletal muscle. This project will develop cell biology in a whole organism rather than a cell culture system and provide a new framework f ....Making muscle: molecular dissection of membrane domain formation. For a muscle to contract efficiently in response to an electrical signal it requires the formation of an extensive system of hollow membranous tubules through which the signal can be propagated. This proposal addresses the molecular mechanisms involved in the formation of this tubule system in skeletal muscle. This project will develop cell biology in a whole organism rather than a cell culture system and provide a new framework for Australian and international cell biologists. It will generate new knowledge, train young Australian scientists, help build international collaborative networks and engage the public outside the research community.Read moreRead less
Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms cont ....Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms controlling this process. We hypothesise that the local environment of a cell is critical and will involve a combination of particular extracellular matrix and growth factors as well as mechanical tension and the presence of other cell types.Read moreRead less
Deciphering The Role Of Atypical DNA Methylation In Neuronal Genome Regulation And Neurological Disorders
Funder
National Health and Medical Research Council
Funding Amount
$773,484.00
Summary
This research will use a combination of genomic, biochemical and functional genomics approaches to investigate the role of the atypical mCH form of DNA methylation in neuronal genome regulation and function, and provide new insights into the role of the epigenome in healthy brain function and neural pathologies.
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.
Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasi ....Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of the damaging effects of UV radiation. A better understanding of the genetic basis of UV-sensitive skin types will greatly enhance the targeting of such skin cancer-prevention campaigns, provide an understanding of changes that occur in skin pathology, and the mechanisms of sun induced tanning.Read moreRead less
Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects withi ....Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects within the cells in culture using live cell imaging, electron microscopy and biochemical analysis. This will provide a molecular basis to explain the pigmentary characteristics of individuals allowing prediction and diagnosis of their photosensitivity with important implications for skin cancer risk.Read moreRead less
The endosome at atomic resolution. The project seeks to improve understanding of intracellular transport. The transport of proteins is essential for controlling the interactions of a cell with its environment, and for regulating a huge number of cell signalling events. The retromer protein complex is a central mediator of intracellular trafficking in organelles called endosomes. It is vital for normal cell homeostasis in all eukaryotic organisms, and is an emerging target for treatment of human ....The endosome at atomic resolution. The project seeks to improve understanding of intracellular transport. The transport of proteins is essential for controlling the interactions of a cell with its environment, and for regulating a huge number of cell signalling events. The retromer protein complex is a central mediator of intracellular trafficking in organelles called endosomes. It is vital for normal cell homeostasis in all eukaryotic organisms, and is an emerging target for treatment of human neurodegenerative diseases. This project plans to use a combination of cutting-edge X-ray crystallographic and electron microscopy approaches to develop a multi-scale, pseudo-atomic structure of retromer and key regulatory proteins to understand how this multi-component protein machinery is assembled to control intracellular transport.Read moreRead less