Recycling Of E-cadherin: Implications For Dynamic Cell Adhesion
Funder
National Health and Medical Research Council
Funding Amount
$250,494.00
Summary
E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During embryonic development E-cadherin is essential for establishing the normal body pattern and the cellular architecture of many epithelial organs. Throughout life E-cadherin serves to maintain epithelial barriers, such as the lining of the digestive tract. E-cadherin has been clearly identified as a tumour suppressor molecule: loss of normal E-cadherin function leads to tumour metastasis and ....E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During embryonic development E-cadherin is essential for establishing the normal body pattern and the cellular architecture of many epithelial organs. Throughout life E-cadherin serves to maintain epithelial barriers, such as the lining of the digestive tract. E-cadherin has been clearly identified as a tumour suppressor molecule: loss of normal E-cadherin function leads to tumour metastasis and cancer invasion. It is therefore essential to understand the physiological function and regulation of E-cadherin in cells. E-cadherin is normally expressed on the surface of cells for adhesion to neighbouring cells. Recently, we found that cells can internalise and recycle this surface E-cadherin: even in mature epithelia, a proportion of the E-cadherin molecules appear to undergo constant movement in and out of the cell. It is likely that this mechanism participates in the dynamic remodelling of adhesive contacts between cells in organs such as the gastrointestinal tract and during wound healing. Corruption of this recycling mechanism could also potentially contribute to tumorigenesis. In this grant we propose to build upon this discovery by investigating molecular and cellular mechanisms that mediate E-cadherin recycling. We will characterize the cellular pathways by which E-cadherin is trafficked. The signaling pathways that regulate recycling will be analysed, since these may be perturbed in cancer and inflammation. Other molecules that interact with E-cadherin will be studied to determine whether they too recycle. The information from these studies will have broad implications for understanding the role of E-cadherin in healthy organs and in common cancers.Read moreRead less
Functional Screening Of Novel Genes In Craniofacial Development
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Our faces are central to our ability to communicate, feed, breath and interact with each other. Birth defects that impact on the normal development of the face are common and affect not only the child but have a dramatic impact on the child's family as well. The genetic causes of most facial birth defects are unknown. This project will develop a method for determining how development of the face is controlled and will help identify genes that are responsible for facial birth defects.
Genetic And Molecular Dissection Of Laterality In The Developing Heart
Funder
National Health and Medical Research Council
Funding Amount
$379,370.00
Summary
Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalitie ....Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalities. In early embryogenesis, the newly-formed heart tube loops to the right, an event which establishes the correct alignment of the future cardiac chambers. The direction of heart looping is determined by genetic pathways that establish laterality in the early embryo. A component of this pathway is a TGFbeta-family signalling molecule, nodal, which is activated on the left side of the forming heart and other organs. Nodal then activates the transcription factor gene Pitx2. The aim of this project is to examine the consequences of genetic inactivation of the mouse nodal and Pitx2 genes in the heart, and to discover cardiac genes downstream of these genes. We will specifically test the hypothesis that laterality contributes to heart chamber formation in addition to setting the direction of looping. Ablation of these genes in the whole embryo leads to complex defects that preclude analysis of their functions in the heart. To achieve heart-specific deletion, we will use a conditional gene ablation technology that exploits the bacteriophage recombinase, Cre. Genes downstream of Pitx2 and Nodal will be discovered using microarray technology, which allows us to screen exhaustively for changes in gene expression between different tissues. This project will help us solve the complex genetic basis of congenital cardiac abnormalities in humans, and will contribute to our understanding of how heart chambers form, potentially useful in stem cell-based therapies for the failing heart.Read moreRead less
Periodontal Mesenchymal Stem Cells For Periodontal Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$358,000.00
Summary
Dental diseases affecting the gums (periodontal disease) are extremely prevalent in our society. The effects of periodontal disease can be particularly severe as loss of support for the teeth leads to loose teeth and severely compromised masticatory function. If left untreated, the associated pain and loss of function may necessitate extraction of the teeth. We have recently identified cells residing in the periodontal ligament which may be adult stem cells. This project will further characteriz ....Dental diseases affecting the gums (periodontal disease) are extremely prevalent in our society. The effects of periodontal disease can be particularly severe as loss of support for the teeth leads to loose teeth and severely compromised masticatory function. If left untreated, the associated pain and loss of function may necessitate extraction of the teeth. We have recently identified cells residing in the periodontal ligament which may be adult stem cells. This project will further characterize these cells and explore whether they can be used to restore periodontal tissues damaged by periodontal disease.Read moreRead less
Dental diseases affecting the gums (periodontal diseases) are extremely prevalent in our society. The effects of periodontal disease can be particularly severe as loss of support for the teeth leads to loose teeth and severely compromised chewing function. If left untreated, the associated loss of function may necessitate extraction of the teeth. We have recently identified cells residing in the periodontal ligament which may be adult stem cells. This project will further characterize these cell ....Dental diseases affecting the gums (periodontal diseases) are extremely prevalent in our society. The effects of periodontal disease can be particularly severe as loss of support for the teeth leads to loose teeth and severely compromised chewing function. If left untreated, the associated loss of function may necessitate extraction of the teeth. We have recently identified cells residing in the periodontal ligament which may be adult stem cells. This project will further characterize these cells and explore whether they can be used to restore periodontal tissues damaged by periodontal disease.Read moreRead less
Periodontal disease is an inflammatory disorder leading to tooth loosening and, if untreated, tooth loss. Once bone destruction has occurred around teeth the treatment outcomes are severely compromised and are mainly focussed towards slowing the process of destruction rather than repairing the damage. Over the last decade, treatment of advanced periodontal disease has focussed on ways in which the damaged tissues may be regenerated. We now have gained considerable insight into the molecular and ....Periodontal disease is an inflammatory disorder leading to tooth loosening and, if untreated, tooth loss. Once bone destruction has occurred around teeth the treatment outcomes are severely compromised and are mainly focussed towards slowing the process of destruction rather than repairing the damage. Over the last decade, treatment of advanced periodontal disease has focussed on ways in which the damaged tissues may be regenerated. We now have gained considerable insight into the molecular and cellular events associated with periodontal regeneration. Despite efforts to induce regeneration through the selective use of growth and differentiation factors it is becoming obvious that the most significant factor in successful clinical outcomes is the recruitment of special cells to the site of damage which have the potential to repair tissue damage. Thus, we intend to engineer different types of periodontal matrices in the laboratory and then transplant these newly formed tissues into sites affected by periodontal disease in an attempt to repair the damage caused by the disease process.Read moreRead less
The Role Of Perlecan In Tensional Connective Tissues
Funder
National Health and Medical Research Council
Funding Amount
$605,037.00
Summary
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their carers. Our project aims to better understand the structure and function of these tissues in health and disease with a view to improving repair strategies.
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