Carnitine Acetyltransferase (CrAT) Regulates Appetite And Body Weight Through The Melanocortin System
Funder
National Health and Medical Research Council
Funding Amount
$547,087.00
Summary
Carnitine metabolism in peripheral tissues, such as muscle, maintains appropriate cellular metabolism and function. Little is known about carnitine metabolism in specific populations of brain cells regulate food intake and appetite. This project aims to understand how carnitine metabolism affect brain cells that regulate food intake and body weight.
Carnitine Palmitoyl Transferase 1 In POMC Neurons Controls Glucose Homeostasis And Body Weight
Funder
National Health and Medical Research Council
Funding Amount
$474,499.00
Summary
The brain plays a critical role in body weight gain by balancing appetite-inducing and appetite-suppressing signals. An imbalance in this process causes obesity, promotes diabetes and cardiovascular disease. The aim of this research is to identify how appetite-suppressing brain signals are maintained as a method to prevent obesity progression.
The role of intracellular calcium in fibre-type specific gene expression in skeletal muscle. Muscles contain different fibre types whose composition can be changed by activity. The aim of this proposal is to identify the intracellular mechanisms which control fibre type. Our hypothesis is that different patterns of intracellular calcium determine the pattern of gene expression which determines fibre type. Understanding how gene expression is regulated is a central issue in biology.
In patients predisposed to metabolic diseases, excessive fats get delivered to various tissues. About 10 to 15% are converted into sphingolipids, many of which have deleterious effects on tissue function. Blocking sphingolipid production prevents diabetes and most cardiovascular diseases in rodents. We seek to better understand these mechanisms and determine how the observations can be translated into new therapies and better clinical outcomes.
Type 2 diabetes is reaching epidemic proportions across the world and is a huge burden in health care costs. We know it is a multifaceted disease with many symptoms, one of which is a reduction in insulin secretion. This proposal sets out to determine the mechanisms of insulin secretion from healthy tissue and what goes wrong in disease.
Role Of AMPK Signaling In Metabolic Control During Exercise
Funder
National Health and Medical Research Council
Funding Amount
$566,288.00
Summary
It is well recognized that sedentary life styles are associated with increased incidence of obesity, Type 2 diabetes and atherosclerotic cardiovascular disease. The medical, social and financial costs of these diseases are growing rapidly and represent a major health care challenge. Exercise is beneficial for maintaining health in patients at risk of developing these diseases and for this reason we are interested in understanding how exercise capacity is regulated.
Manipulating Store-operated Ca2+ Entry To Improve Muscle Function In Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$516,163.00
Summary
Muscle function is regulated in a complex manner by calcium and is impaired in Duchenne muscular dystrophy (DMD). Changes in calcium regulation will be investigated in DMD patients and in an animal model using a novel approach. We will use a combination of novel experimental approaches to manipulate muscles in dystrophic mice and test for improvement in function. Results will determine the viability of a potential treatment.
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
Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology ....Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology, Ca2+ regulation and optical membrane potentiometry allow us to monitor early changes in disease on a (sub)cellular level. Experiments on Ca2+ regulation and ion channel function in muscle with different cholesterol membrane contents will help to understand pathomechanisms in high cholesterol diseases, e.g. obesity, on the membrane level long before cardiovascular effects become prominent.Read moreRead less
Origin Of Cells In The 'artificial' Artery Grown In The Peritoneal Cavity
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the s ....Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the structure of the surrounding tissue and the myofibroblasts differentiate further into functional smooth muscle. This raises the question: what is the origin of the cells of the capsule? Our previous studies suggested that monocyte-macrophages stimulated to enter the abdominal cavity in response to the sterile foreign body might be the source of the cells. In the current study we will use transgenic (c-fms EGFP and c-fms Cre Z-AP) mice in which cells of monocyte-macrophage lineage are genetically labelled. These cells can be clearly distinguished from all other cells of the body, and analysis of capsules formed around foreign bodies will give us a definitive answer. We will using micro-array analysis, determine which growth factors-cytokines are important in regulating differentiation of the cells, and the role of physical factors (eg pulsatile stretching). Finally, we will determine whether these cells stimulated to enter the abdominal cavity are capable of differentiating along alternative pathways, such as cardiac muscle or liver cells. Knowledge gained will further the use of the abdominal cavity as a bioreactor in which to engineer tissues for organ replacement therapies. Identification of the mechanisms regulating the (trans)differentiation and biology of the cells may also assist in wound repair strategies to prevent pathologies caused by excessive myofibroblast accumulation and fibrosis.Read moreRead less