Early Events In Arteriolar Remodeling: Adaptation To Prolonged Vasoconstriction
Funder
National Health and Medical Research Council
Funding Amount
$415,750.00
Summary
Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes ....Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes within the vessel wall (for example thickening of the muscle layer). These adaptive processes may enable the forces of contraction to be maintained without continued energy expenditure and damage to the vessel per se. However, they can also contribute to long-term alterations in the control of blood pressure and perhaps contribute to states of hypertension as well as other common vascular diseases. For these studies we will use arterioles, isolated by microsurgical techniques, together with sophisticated computer and video-based approaches. These techniques allow arterioles to be studied under controlled conditions and relevant biochemical measurements performed. We will also use a cell model where cultured cells will be studied after defined periods of mechanical stimulation (for example stretch). Cells will be probed using a novel microscopic technique (atomic force microscopy) which enables the cell membrane to be studied with respect to changes in composition as well as physical characteristics (for example stiffness). The studies are relevant to our understanding of the normal adaptive processes occurring within blood vessels to control blood flow and pressure. The studies are also of direct relevance to our understanding of common vascular disease states including hypertension, complications of diabetes and chronic inflammatory disorders.Read moreRead less
Primary Cardiac Hypertrophy - A Functional Genetic Approach To Investigate Cellular Mechanisms Of Metabolic Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$226,692.00
Summary
Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal m ....Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal model to study the function of single heart cells. In this model one of the glucose transporters has been deleted. Our goal is to compare heart function in this genetic model with heart function in diabetes. Cells are isolated from hearts using enzyme treatments and investigated microscopically to determine if there are subcellular structural alterations. Functional studies are performed on individual viable cells using a combination of electrical recording techniques and fluorescence imaging methods. The experimental aim is to assess whether there is disruption of sodium, calcium or pH regulation associated with cardiac enlargement associated with metabolic abnormalities. This research will assist in identifying appropriate therapeutic strategies for intervention in the treatment or prevention of conditions associated with cardiac enlargement.Read moreRead less
Parathyroid Tumorigenesis - A Role For The Newly Identified Putative Tumour Suppressor HRPT2
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Primary hyperparathyroidism is one of the most common tumour associated diseases of hormone secreting glands affecting 0.1-0.5% of adults and up to 3.4% of post-menopausal women. It can occur in family members, either alone or with other tumours, and can also occur with no family history (sporadic). Hyperparathyroidism is caused by secretion of excessive levels of parathyroid hormone. Amongst other problems, this causes significant bone disease that can lead to fracture. What is going wrong at t ....Primary hyperparathyroidism is one of the most common tumour associated diseases of hormone secreting glands affecting 0.1-0.5% of adults and up to 3.4% of post-menopausal women. It can occur in family members, either alone or with other tumours, and can also occur with no family history (sporadic). Hyperparathyroidism is caused by secretion of excessive levels of parathyroid hormone. Amongst other problems, this causes significant bone disease that can lead to fracture. What is going wrong at the genetic level to cause this disease is, in most cases, poorly understood. In Hyperparathyroidism Jaw Tumour Syndrome (HPT-JT), one form of familial hyperparathyroidism, we and our international collaborators have recently identified mutations in the gene HRPT2 predicted to lead to loss of function of this gene. HRPT2 has no known similarities to other genes that may give hints as to its function. The overall aim of this project is to test our theory that HRPT2 has an important role in abnormal growth of parathyroid tissue that, in some cases, will lead to cancer. Further, we hypothesise that this gene will have a role in both familial and sporadic presentations of parathyroid disease. We will investigate this gene in parathyroid tumour specimens from patients with familial and sporadic disease for gene mutations and also different levels of gene expression. We will also explore a mechanism for how these mutations may function to cause disease and look at the effect of reduced HRPT2 expression on expression of thousands of other genes using a technique known as microarray analysis. The expected outcomes of this study include the identification of individuals at risk of developing cancer whose treatment will be tailored to their genetic profile. Characterisation of HRPT2, and the genes its expression influence, may lead to the identification of suitable targets for future treatment of hyperparathyroidism and its effects on bone disease.Read moreRead less