Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less
Improved Ex-vivo Culture Of Keratinocytes For Clinical Applications
Funder
National Health and Medical Research Council
Funding Amount
$275,203.00
Summary
Skin cells grown for clinical applications currently require animal-derived cells and-or non-defined products for their expansion in the laboratory; these reagents can potentially infect patients who receive these therapies. This project will identify the essential components provided by these reagents and develop a fully synthetic and defined culture system. This improvement will provide safer, cost-effective grafts and cell-based therapies that will benefit patients suffering burns and wounds.
Optimizing Implanted Cell Survival Using A Tissue Engineering Model
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Cell therapy and tissue engineering involve the insertion of specific cells into damaged tissues or into a bioraector in a patient's body to generate new replacement tissues. This project seeks to improve two factors associated with inserting cells : 1. The innate survival characteristics of the cells being inserted, and 2. The blood vessel supply at the site of insertion. These techniques will greatly improve the survival of inserted cells.
Developing In Vivo Methods Of Adipose Tissue Engineering
Funder
National Health and Medical Research Council
Funding Amount
$374,703.00
Summary
Surgical repair and replacement of soft tissues after tumour removal or to repair existing damage requires fat tissue with a good blood supply. Tissue engineering allows us to create new fat grafts for replacement tissue without causing unnecessary pain or trauma to the patient. We have developed a method for growing fat tissue using a chamber to maintain a space for the tissue to grow into, a blood vessel to supply nutrients to the growing tissue, cells or tissue from the host to encourage cell ....Surgical repair and replacement of soft tissues after tumour removal or to repair existing damage requires fat tissue with a good blood supply. Tissue engineering allows us to create new fat grafts for replacement tissue without causing unnecessary pain or trauma to the patient. We have developed a method for growing fat tissue using a chamber to maintain a space for the tissue to grow into, a blood vessel to supply nutrients to the growing tissue, cells or tissue from the host to encourage cell growth and migration and a matrix or scaffold to support the developing tissue and guide it to form the type of tissue we want (fat, muscle etc). We have shown that the tissue graft may cause fat to grow due to causing an inflammatory reaction and confirmed this by adding a mild inflammatory compound to the chamber instead of a tissue graft. This compound caused the chamber to grow fat tissue. The aim of this project is to determine which of the growth factors or other signaling factors released by the inflammation process is responsible for causing fat tissue production and to identify what cells are being attracted to the chamber to help grow the fat, so that we can further improve our engineering of fat tissue. Understanding the pathways which mediate or stimulate fat growth will provide new opportunities for improving fat growth and allow the engineering of larger fat grafts in larger animals and eventually human clinical application. Beyond that, inflammation is involved in many disease processes (eg. obesity, metabolic syndrome, diabetes, cancer), and these fields of study will also benefit from our research.Read moreRead less
Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western soc ....Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western societies (namely acid reflux, obesity and poor diet), there are strong grounds for predicting that incidence will continue to rise, and that oesophageal cancer will constitute an increasingly large burden on society. Unfortunately, treatment options are limited, survival is often short, and there is no way of identifying which tumours will respond to therapy. This proposal will collect treatment and health outcomes data for a population-based cohort of patients with oesophageal cancer. The goal is to identify prognostic and predictive markers to aid patients and clinicians when making treatment decisions, as now exist for breast cancer. Such markers may also serve as novel targets for therapy. The proposed study builds upon the platform of the Australian Cancer Study [ACS], one of the world's largest studies of oesophageal cancer. This represents a unique opportunity to investigate a pressing clinical problem by building upon a study of acknowledged international importance.Read moreRead less
Engineering Tissues And Organs In Vivo From Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,480.00
Summary
Tissue engineering is an exciting new area of medical research. We have developed a unique animal model of tissue engineering where new tissue spontaneously sprouts from the surface of a vascular loop enclosed inside a plastic chamber. The tissue thus created has its own blood supply. By adding cultured cells or altering the environment of the chamber we have been able to grow new specific tissues such as fat and muscle. This technology potentially allows the generation of spare body parts to re ....Tissue engineering is an exciting new area of medical research. We have developed a unique animal model of tissue engineering where new tissue spontaneously sprouts from the surface of a vascular loop enclosed inside a plastic chamber. The tissue thus created has its own blood supply. By adding cultured cells or altering the environment of the chamber we have been able to grow new specific tissues such as fat and muscle. This technology potentially allows the generation of spare body parts to replace lost or worn out organs and tissues. We have recently reproduced this model in the mouse to be able to screen a range of mouse and human stem cells. These cells have the ability to change (i.e. differentiate) into many different types of cell depending on how they are stimulated. In Part 1 of this project we will determine in the mouse chamber the growth characteristics and survival rates of these stem cells. A chamber encapsulating a flowing blood vessel will be implanted subcutaneously in each groin. In one chamber we will inject fluorescently labelled stem cells in a growth medium and in the other growth medium alone. Tissue will be analysed at 1, 2 and 4 weeks. In Part 2 we will inject a variety of Rosa26 labelled mouse stem cells obtained from several different tissues. Through the aid of naturally occurring growth and differentiation factors they will differentiate into one of several different tissues including fat, cartilage, bone, neural tissue, blood vessels, liver, etc, which will be identified by histology and cell culture. In one experiment we will genetically alter cells injected into the chamber so that they produce only skeletal muscle. In Part 3 we will grow new human tissues by injecting human stem cells into the same tissue engineering chambers in mice which will tolerate cells from other mammals (these are known as SCID mice). Success in novel method would be the precursor for the production of new human tissues to repair specific defects.Read moreRead less
NON IMMUNOLOGICAL BARRIERS TO SUCCESSFUL TREATMENT OF DIABETES BY XENOTRANSPLANTATION
Funder
National Health and Medical Research Council
Funding Amount
$310,500.00
Summary
Tragically patients whom suffer from diabetes mellitus develop major secondary complications such as renal failure, even with today's tight glucose control. Insulin injections minimise diabetic complications but restricts lifestyle and an alternative, pancreatic islet cell transplantation, is limited by donor shortage. With genetic technology, pig donor tissue is a feasible donor source. This project will use an inbred pig colony to assess long term pig fetal and neonatal islet cell function in ....Tragically patients whom suffer from diabetes mellitus develop major secondary complications such as renal failure, even with today's tight glucose control. Insulin injections minimise diabetic complications but restricts lifestyle and an alternative, pancreatic islet cell transplantation, is limited by donor shortage. With genetic technology, pig donor tissue is a feasible donor source. This project will use an inbred pig colony to assess long term pig fetal and neonatal islet cell function in combination with a kidney graft in the absence of an immune response. Using this specifically inbred pig colony we will carefully catalogue the type, number and distribution of endogenous retroviruses within pig genes. Using new and novel techniques we will develop a new strategy by which we can block and overcome this major concern of xenotransplantation. Ultimately a unique Australian resource will be developed which may provide unlimited islets for safe, large-scale transplantation of diabetics before they develop debilitating secondary complications from their diabetes and provide an alternative to the only current method of curing endstage renal failure with a combined pancreas and kidney transplant.Read moreRead less