Function Of The S100A1 Ca2+-binding Protein Under Physiological And Pathological Conditions
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal condi ....The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal conditions, and how it contributes to the development of heart failure. Preliminary data indicate that adult mice with reduced S100A1 protein levels develop a form of heart disease that significantly reduces the efficiency of the pump function of the heart.Read moreRead less
Transcriptional Regulatory Complexes Associated With Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression. It has been well known that a group of genes are altered (up or down) in the heart under conditions such as heart muscle overgrowth (ie ....Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression. It has been well known that a group of genes are altered (up or down) in the heart under conditions such as heart muscle overgrowth (ie hypertrophy), aging or of abnormal beating function. The reasons for such altered gene activity remain poorly understood. Although recent studies from research on genetics or cancer have revealed the important role of the DNA and DNA-bound proteins (called histone) in the control of gene activity, this has rarely been studied in the heart. In this project, we will test our hypothesis that DNA-histone structure is a key factor that control gene activities in ageing and diseased heart. This proposal is supported by our recent findings showing that in the hypertrophied heart, such DNA-histone structure did alter in such a way that fits well with alterations in gene activity. We have planned a series of studies to test this hypothesis in a systematic fashion. A number of sophisticated and cutting-edge techniques and experimental models of heart hypertrophy will be used. We will analyse changes in activities of a number of selected genes in the heart and also analyse changes in DNA-histone structures and chemical modifications at particular regions. These changes will then be linked together. We will also explore the possibility of modulating DNA-histone structure, thereby controlling the degree of cardiac hypertrophy. This project is the joint efforts of scientists with substantial experience in research on gene activity and heart diseases, and is highly likely to generate novel information to and hold significant therapeutic potential.Read moreRead less
Heart muscle cells have little potential for regeneration, and after a heart attack or in response to chronic hypertension, they grow bigger, resulting in deterioration of function and heart failure. We have compelling evidence that the c-kit protein limits heart regeneration and function. We expect to demonstrate that c-kit inactivation can greatly improve heart regeneration and function after cardiac injury/stress. Our work will have major clinical significance for future heart failure treatme ....Heart muscle cells have little potential for regeneration, and after a heart attack or in response to chronic hypertension, they grow bigger, resulting in deterioration of function and heart failure. We have compelling evidence that the c-kit protein limits heart regeneration and function. We expect to demonstrate that c-kit inactivation can greatly improve heart regeneration and function after cardiac injury/stress. Our work will have major clinical significance for future heart failure treatment strategies.Read moreRead less
Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cel ....Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cells can affect how much calcium flows through these calcium channels. The proteins were thought to have other functions and our discovery of their effect on ryanodine receptor calcium channels has caused considerable excitement. We now plan to explore how they do this. We will mutate specific regions of the proteins to discover which regions are important and which are not. We will also look at whether closely related proteins have similar effects. The new class of ion channel modulator that we are studying has the capacity to alter not only respiration, movement and cardiac contraction, but also other aspects cardiovascular function, neuronal activity and immune responses. Understanding the way in which soluble proteins can interact with ion channels may reveal a novel target for drugs that affect ryanodine receptor calcium channel function and allow the rational design of specific drugs to regulate ion channels or ion channel modulators.Read moreRead less
Vasomotor Ganglionic Transmission: The Preganglionic Peptide And The Second Gear
Funder
National Health and Medical Research Council
Funding Amount
$451,896.00
Summary
Blood pressure depends on nerve signals that travel from the central nervous system to blood vessels. In the middle of this pathway is a relay station - the sympathetic ganglion cell. Transmission through this relay station has recently been shown to have not only a fixed but also a variable component - the 'second gear'. The project tests if and how three likely candidate peptide molecules, one in the nerves, two in the bloodstream, control this 'second gear' and hence regulate blood pressure.
(a) Pathogenesis Of Aortic Stenosis : Relationship To Valvular Endothelial Function.
Funder
National Health and Medical Research Council
Funding Amount
$254,995.00
Summary
In the 21st century, heart disease will continue to be a major cause of disability and death in Western society. However, the relative decline in the frequency of premature death due to coronary disease (such as heart attacks) combined with increases in longevity, will see the emergence of new disease states. Aortic stenosis (AS) is likely to be one of the most important of these: progressive aortic valvular narrowing, culminating in the development of heart failure, and cardiac death. To date, ....In the 21st century, heart disease will continue to be a major cause of disability and death in Western society. However, the relative decline in the frequency of premature death due to coronary disease (such as heart attacks) combined with increases in longevity, will see the emergence of new disease states. Aortic stenosis (AS) is likely to be one of the most important of these: progressive aortic valvular narrowing, culminating in the development of heart failure, and cardiac death. To date, the only established treatment for severe AS is valve replacement. The incidence of AS increases with age: approximately 40% of individuals over the age of 80 have some AS, while 4% have severe AS. Studies to date have revealed that AS is more likely to occur (and to progress rapidly) in patients with impaired kidney function, and that some coronary risk factors (high cholesterol levels and diabetes, for example) also predispose to AS. The planned research will examine the potential role of the (endothelial) cells lining the aortic valve in protecting against the development of AS. In particular, we will try to identify which chemicals interfere with endothelial function, and how this leads to thickening of the valve. The ulitmate objective of this research is to delineate the chemical factors causing AS, in order to help in the development of preventative strategies for this disease.Read moreRead less