Understanding Vasoactive Hormone Pathways In Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$453,750.00
Summary
High blood pressure damages tissues. In clinical practice blood pressure is measured in large arteries, such as the brachial artery in the arm. However, it is the pressure within the organ such as the kidney that actually causes the damage. In particular, the sieving apparatus of the kidney (called the glomerulus), is especially sensitive to the effects of pressure. In diabetes, the pressure within the glomerulus is high because its outflow valve (called the efferent arteriole) is tightly constr ....High blood pressure damages tissues. In clinical practice blood pressure is measured in large arteries, such as the brachial artery in the arm. However, it is the pressure within the organ such as the kidney that actually causes the damage. In particular, the sieving apparatus of the kidney (called the glomerulus), is especially sensitive to the effects of pressure. In diabetes, the pressure within the glomerulus is high because its outflow valve (called the efferent arteriole) is tightly constricted. Therefore even if blood pressure is thought to be normal when measured in the arm, it may still be excessively high within the kidney. Studies have already shown that lowering within-kidney pressure may have a major impact on the progression of kidney disease in diabetes. However, to date this reduction of within-kidney pressure has been sub-maximal. The planned studies will involve the use of new compounds which have more powerful effects in reducing the formation or action of hormones which promote constriction of vessels in the kidney leading to elevated pressure within the kidney. Furthermore, some of these very new agents can open up or dilate these kidney vessels thereby achieving excellent reductions in the pressure inside the kidney. The proposed studies aim to examine new strategies for preferentially lowering pressure within the kidney down to these ideal levels. These hormones also have other effects which could be relevant to non-kidney sites of injury in diabetes including blood vessels and the retina.Read moreRead less
The Role Of Vasoactive Hormones In Progressive Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$453,750.00
Summary
Cirrhosis of the liver is a leading cause of morbidity and mortality in our community and its prevalence is rising due to the increasing impact of chronic viral hepatitis infection. While the advent of effective antiviral therapies will have some benefit in reducing this disease burden, there remains a major need to develop treatments that can prevent and treat cirrhosis of the liver and its clinical sequelae. We believe that overactive hormone systems may play a role in disease of the liver. Th ....Cirrhosis of the liver is a leading cause of morbidity and mortality in our community and its prevalence is rising due to the increasing impact of chronic viral hepatitis infection. While the advent of effective antiviral therapies will have some benefit in reducing this disease burden, there remains a major need to develop treatments that can prevent and treat cirrhosis of the liver and its clinical sequelae. We believe that overactive hormone systems may play a role in disease of the liver. The planned studies will involve compounds that block the formation or the action of hormones which cause scarring of the liver. The results may lead to new treatments for cirrhosis of the liver.Read moreRead less
The West Nile Viral Protease, NS3: A Target For Antiviral Drug And Vaccine Design
Funder
National Health and Medical Research Council
Funding Amount
$230,500.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Midd ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003) have been characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid-westnile-index.htm). No treatments or vaccines are available. This project focuses on an enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that can block its function and these have real potential as leads for development of drug treatments for people infected by this virus. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections. Our studies will also be used to develop potential vaccines. The science involves experts on protease enzymes, drug design and development, virology including West Nile virology, and vaccine development. We expect to generate drug and vaccine candidates and new information for their development that is at the cutting edge of West Nile Virus research.Read moreRead less
The Role Of Proteinase Inhibitor 9 In Cytotoxic Lymphocyte Function
Funder
National Health and Medical Research Council
Funding Amount
$820,136.00
Summary
Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are a ....Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are aimed at understanding the role of the inhibitor in human immune and reproductive function. We will also design and evaluate synthetic compounds based on the natural inhibitor that will enable us to easily measure granzyme B levels and control its activity.Read moreRead less