(Re)wiring A Stem Cell: Deciphering The Molecular Mechanism Underpinning Lineage Propensity
Funder
National Health and Medical Research Council
Funding Amount
$855,780.00
Summary
This project explores the response of the stem cells to cues that direct how they turn into specific type of cells that is suitable for clinical use. Specifically, a set of driver genes whose activity can foretell the outcome of cell differentiation will be identified. By modulating the maintenance conditions, iPSCs lines may be tailored for specific applications in stem cell therapy and disease modelling for the assessment of treatment efficacy.
Reprogramming is the conversion of any cell into induced pluripotent stem cells (iPSC). iPSC carry immense clinical potential as they are pluripotent and can hence form any cell of the human body, however, they can also form tumours. We have identified a cell type during reprogramming which is pluripotent but cannot form tumours. It is the aim of this project to determine the molecular differences between iPSC and this cell type in order to facilitate the delivery of cell replacement therapies.
The Role Of Hyaluronic Acid In The Biology Of Haemopoietic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$392,090.00
Summary
Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules (CAM). This project is based upon the unique observation made in the applicants laboratory demonstrating that both murine HSC and candidate human HSC synthesize the carbohydrate CAM hyaluronic acid (HA). Moreover w ....Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules (CAM). This project is based upon the unique observation made in the applicants laboratory demonstrating that both murine HSC and candidate human HSC synthesize the carbohydrate CAM hyaluronic acid (HA). Moreover we have now accumulated data suggesting a key role for HA in determining the spatial distribution of HSC within the BM following transplantation and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current inability to identify HSCs in situ makes it impossible to analyse either their distribution or molecules that regulate this process. Circumstantial evidence suggests the presence of HSC niches in close association with the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the first to report that the lodgment of a transplant of HSC is not a random process, but results in cells of donor origin being located at the bone-marrow interface. The presence of HA on HSC was critical for this pattern of lodgment. In addition, we have also accumulated evidence suggesting that HA is important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical role of HA in HSC biology.Read moreRead less
Investigating The Transcriptional Circuitry Of Normal Human Haematopoietic And Leukaemic Cells
Funder
National Health and Medical Research Council
Funding Amount
$698,797.00
Summary
Despite improvements in supportive care, more than half the patients diagnosed with acute myeloid leukaemia (AML) succumb to complications associated with the disease or its treatment. To improve treatment outcomes, we need to understand how leukaemic cells self-renew and how this differs from normal blood stem cells. Our proposal aims to do this by using computational and experimental methods to identify and validate factors to which leukaemic cells are more dependent than normal blood cells.
Dissecting The Molecular Mechanisms During Reprogramming Of Different Somatic Cells Into Induced Pluripotent Stem Cells And The Plasticity Potential Of Their Intermediate Stages.
Funder
National Health and Medical Research Council
Funding Amount
$234,965.00
Summary
I am a biochemist interested in the molecular mechanisms involved in gene expression and how these processes govern cell identity. I use a combination of mouse models, biochemical techniques and bioinformatics to study the _reprogramming� of adult cells into embryonic stem-like cells and how this technology can be used to generate different cell types for use in cellular replacement therapies and drug screening.
Function Of The Lysophospholipid Receptor Family In Neuronal Stem Cells And Their Progenitors.
Funder
National Health and Medical Research Council
Funding Amount
$380,723.00
Summary
Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor ....Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor cells of the lysophospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), bioactive molecules known to play an essential role in the nervous system during development and inflammation. Our project aims to understand the mechanisms of action of these molecules in NSC maintenance, proliferation, differentiation and migration. By understanding how these molecules are able to regulate NSC biology will provide new avenues in the development of tools necessary for stem cell therapy.Read moreRead less
Mechanisms Of Resistance To Immunological Targeting Of Primary And Metastatic Colorectal Cancers
Funder
National Health and Medical Research Council
Funding Amount
$612,828.00
Summary
The immune system influences the outcome in patients with cancer. We have been early adopters of immunotherapy approaches to target cancer cells using the novel approaches to enhance immune attack on cells that aberrantly express cancer regulators. These represent drivers to which cancer cells are addicted. A central tenant of optimizing immunotherapies has been to employ immune stimuli in concert with removing immune blocking systems. Our research plan is to improve immunotherapy efficiency.
Regulation Of Haematopoietic Stem Cells Through Histone Modifications
Funder
National Health and Medical Research Council
Funding Amount
$797,014.00
Summary
The genetic material is packaged in the cell nucleus with histone proteins. Modifications of histones determine if a particular area of the genome is active or repressed. We are investigating a family of histone modifying proteins, the MYST proteins. Mutations in these proteins cause intellectual disability and blood cancer. In this project we examine the role of MYST2 in blood stem cells. Knowledge gained may become the basis for the development of drugs for the treatment of cancer.