The Role Of Tissue Factor In The Regulation Of Extracellular Matrix Remodelling And Angiogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal me ....The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal menstrual cycle, and for the normal growth and development of the placenta and a new baby. The processes by which these new blood vessels form and the factors contributing to the maintenance of their structure are incompletely understood. However, it is known that the interaction of cells and the surrounding extracellular matrix is critical for normal cell function and in particular for new blood vessel formation. Studies in this project will seek to define a relationship between some of the factors which regulate blood clotting, and those that regulate turnover of the extracellular matrix and new blood vessel formation. In particular, how blood clotting factors may be invovled in the regulation of the extracellular matrix will be studied in a rapidly developing tissue, the mouse placenta. The role of blood clotting factors in regulation of new blood vessel formation into an artificial avascular tissue will also be examined. These studies will employ some of the new genetic techniques to understand new roles for proteins which have been traditionally thought to act in only one way. This research has the potential to provide new insights into how blood vessels are formed and are subsequently maintained. This increased understanding will provide the knowledge required for the development of new therapeutic strategies to correct the process when it goes wrong, is unwanted or underdeveloped in human disease.Read moreRead less
The Role Of SPARC In Intestinal Extracellular Matrix Changes And Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$526,728.00
Summary
The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer ....The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer that complicated these conditions. Healing of the bowel inflammation can result in scarring. Whether scarring develops or not hinges on the balance between tissue production and destruction. If production outstrips destruction then scarring may occur, but if this balance can be modified in favour of reduced production then, potentially, healing may proceed without scarring. This project aims to investigate the role of a protein, SPARC, that can regulate scar formation and its interactions with other proteins that can alter scar formation in a mouse model of chronic bowel inflammation. Chronic inflammation of the bowel can also cause the development of colon cancer. Colon cancer is one of the most common cancers in the Australian population. The level of SPARC in the colon cancer at time of initial surgery may predict the risk of disease recurrence. The aim of this study is to determine if SPARC levels can identify those patients at higher risk of cancer recurrence. The role of SPARC will also be examined in a mouse model of colon cancer to determine if increased SPARC levels increased or decrease the rate of cancer growth and its spread.Read moreRead less
Role Of Mast Cells And Their Chymases In The Development Of Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$378,000.00
Summary
Cardiac hypertrophy or heart enlargement is an important risk factor in the eventual development of heart failure. It is now well known that heart enlargement can be produced by pressure overload of hypertension and-or by increased hormonal inputs directly to the heart. Angiotensin ll, a hormone that produces hypertension and heart enlargement, was previously thought only to be produced by the enzyme ACE. Although ACE inhibitors are widely used in treatment of hypertension and heart failure seve ....Cardiac hypertrophy or heart enlargement is an important risk factor in the eventual development of heart failure. It is now well known that heart enlargement can be produced by pressure overload of hypertension and-or by increased hormonal inputs directly to the heart. Angiotensin ll, a hormone that produces hypertension and heart enlargement, was previously thought only to be produced by the enzyme ACE. Although ACE inhibitors are widely used in treatment of hypertension and heart failure several studies now show that ACE inhibition only partially reduces angiotensin ll levels in humans. Our ecent studies suggest that the novel enzyme human chymase may be involved in regulating angiotensin ll levels in human tissues including the heart and blood vessels. The proposed studies seek to establish the role of chymase, and the cell type (mast cell) that elaborates it, in the development of cardiac hypertrophy.Read moreRead less
A Transgenic Mouse Model For Studying The Role Of Human Chymase In Regulating Tissue Angiotensin II Formation
Funder
National Health and Medical Research Council
Funding Amount
$536,063.00
Summary
Cardiac hypertrophy or heart enlargement is an important risk factor in the eventual development of heart failure. It is now well known that heart enlargement can be produced by pressure overload of hypertension and-or by increased hormonal inputs directly to the heart. Angiotensin II, a hormone that produces hypertension and heart enlargement, was previously thought only to be produced by the enzyme ACE. Although ACE inhibitors are widely used in treatment of hypertension and heart failure seve ....Cardiac hypertrophy or heart enlargement is an important risk factor in the eventual development of heart failure. It is now well known that heart enlargement can be produced by pressure overload of hypertension and-or by increased hormonal inputs directly to the heart. Angiotensin II, a hormone that produces hypertension and heart enlargement, was previously thought only to be produced by the enzyme ACE. Although ACE inhibitors are widely used in treatment of hypertension and heart failure several studies now show that ACE inhibition only partially reduces angiotensin II levels in humans. Our recent studies suggest that the novel enzyme human chymase may be involved in regulating angiotensin II levels in human tissues including the heart and blood vessels. By introducing a gene for human chymase in mice we plan to create a mouse model that allows us to understand the importance of human chymase in cardiovascular physiology and disease. This mouse model would not only show the involvement of human chymase in regulating heart and vessel angiotensin II levels and in the development of hypertension and heart enlargement but also will provide an animal model essential for the development of human chymase inhibitors.Read moreRead less