Identification Of Heterogeneity In Vasodilator Function In Human And Rat Resistance Vessels: Potential Drug Targets?
Funder
National Health and Medical Research Council
Funding Amount
$595,330.00
Summary
The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not w ....The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not well understood. While current drugs for treating vascular disease either reduce vessel constriction or increase dilation, they are not specific for individual arteries; a situation that would allow us to control vascular diseases in a very specific manner. Recently, we have described differences between the ways that individual vessels are controlled. These changes relate to differences in the way that different vessels dilate. AIMS - To further understand normal blood vessel function and the changes that occur in blood vessels in cardiovascular disease, with a focus on the ways that blood vessels dilate in normal states and in obesity-related diseases, such as in hypertension and diabetes. - The eventual aim is to identify the specific ways that arteries function, so that artery-specific drug targets can be identified to treat disease-related changes in cardiovascular disease in a very specific manner. EXPECTED OUTCOMES This project will contribute to understanding blood vessel function in health and disease. The expected eventual outcome is the identification of the mechanisms that underlie the function of different arteries in different parts of the body, so that specific individual vessel function can be targeted to treat vascular disease. Additionally, this work will also verify the relevance of the diet-induced obesity animal model, in terms of the characteristics and causes of human obesity and related cardiovascular disease.Read moreRead less
Reproduction is dependent upon the secretion of gonadotropin releasing hormone (GnRH) from the brain, that stimulates gonadotropin synthesis and release from the pituitary gland. In turn, GnRH and gonadotropin secretion is controlled by feedback effects of gonadal steroids such as estrogen. Various neural systems regulate GnRH cells. Kisspeptin is a recently discovered neuropeptide that appears to play a major role in the regulation of GnRH cells. Because it is newly recognized, the significance ....Reproduction is dependent upon the secretion of gonadotropin releasing hormone (GnRH) from the brain, that stimulates gonadotropin synthesis and release from the pituitary gland. In turn, GnRH and gonadotropin secretion is controlled by feedback effects of gonadal steroids such as estrogen. Various neural systems regulate GnRH cells. Kisspeptin is a recently discovered neuropeptide that appears to play a major role in the regulation of GnRH cells. Because it is newly recognized, the significance of kisspeptin and the relevant receptor, GPR54, is not well defined. This project aims to use our unique combination of abilities to determine the significance of kisspeptin in the regulation of GnRH and gonadotropin secretion. We will study both sheep and monkey brains, measuring gene expression for kisspeptin and GPR54 in a range of physiological states and we will determine how kisspeptin acts on GnRH cells. We will determine whether kisspeptin plays a role in the feedback effects to GnRH cells. Effects on the pituitary gland will also be studied. We will use sheep models to measure kisspeptin effects on GnRH secretion, because this cannot be done in the monkey or the rodent. We will examine the function of kisspeptin and GPR54 in relation to puberty. We will also use a model of puberty (seasonal breeding in the sheep) to determine whether activation and quiescence of the reproductive system is related to the function of kisspeptin and GPR54. This work will define the role of kisspeptin in the regulation of reproduction.Read moreRead less
Mechanisms Involved In Reduced Cardiac Contractility As A Consequence Of Growth Restriction During Fetal Development
Funder
National Health and Medical Research Council
Funding Amount
$317,810.00
Summary
Functional development of the heart muscle has been a focus of intense research over the last 40 years. Despite our current understanding of the changes in how excitation of the cardiomyocyte leads to contraction, a process broadly termed excitation-contrcation (E-C) coupling, a major model used to study paralells of human fetal development, the sheep, has not been examined in this context. As such, it remains unclear how E-C coupling evolves from the fetus to the adult. Understanding normal phy ....Functional development of the heart muscle has been a focus of intense research over the last 40 years. Despite our current understanding of the changes in how excitation of the cardiomyocyte leads to contraction, a process broadly termed excitation-contrcation (E-C) coupling, a major model used to study paralells of human fetal development, the sheep, has not been examined in this context. As such, it remains unclear how E-C coupling evolves from the fetus to the adult. Understanding normal physiology is imperative to subsequetly understand pathological states, such as interuterine growth restriction (IUGR). In Australia, the incidence of IUGR leading to low birth weight babies is 7%. IUGR is caused by maternal undernutrition, maternal smoking-drug use and placental insufficiency. It is associated with an increase in perinatal mortality, respiratory problems, SIDS and morbidity. Epidemiological studies show that low birth weight babies are also at an increased risk of cardiovascular disease, including heart failure, in adult life. To date, there is little information on the impact of fetal growth restriction on the normal development and function of the heart muscle. Understanding the impact of IUGR on heart muscle development will allow the elucidation of the underlying physiological mechanisms linking these two temporally distinct events. This mechanistic understanding will allow improved clinical management of those individuals at risk of cardiovascular disease in adult life arising from IUGR. It may also allow for early intervention strategies that can improve cardiovascular function. Therefore, we propose to examine both the normal developmental changes to E-C coupling so that we can understand how placental insufficiency leading to IUGR impairs normal heart muscle development. This will result in impaired function at a cellular level, which will ultimately manifest as an increased susceptibility of the heart to injury in later life.Read moreRead less
A lack of oxygen in the kidney (hypoxia) is a primary cause of kidney disease, but the mechanisms are not clear. To determine the processes involved, we will take a new approach; combining a mathematical model with studies of kidney oxygen regulation in both normal and diseased kidneys. We will determine the causes of hypoxia in kidney disease, and find out if preventing hypoxia has the potential to be a treatment for kidney disease.
Understanding The Metabolic Consequences Of Impaired AMPKa2 And NNOS� In Skeletal Muscle: Implications For The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$575,527.00
Summary
The inability of muscle to utilise sugar from the blood is a major problem that contributes to obesity and Type 2 diabetes. Since the number of people with these diseases will at least double by 2030, we need to find out what causes this problem. We will examine whether two muscle proteins that are impaired in obesity and Type 2 diabetes are also responsible for impaired sugar utilisation. We think that increasing these muscle proteins will fix the _sugar problem�, and remedy these diseases.
Muscle Thermogenesis In Models Of Predisposition To Obesity
Funder
National Health and Medical Research Council
Funding Amount
$469,289.00
Summary
Obesity is a major health crisis, but effective treatments remain elusive. Body weight is determined by a balance of food intake and energy expenditure. Understanding both sides of this equation is essential to combating obesity. This project will show that the rate at which muscle uses energy is an important determinant of energy balance and contributes to the propensity to become obese. The work will define muscle as a target for developing anti-obesity therapies.
Intrinsic Response Of Airways To Cyclical Dilation And Elongation In Breathing
Funder
National Health and Medical Research Council
Funding Amount
$355,014.00
Summary
Variations in lung pressures during breathing produce cyclical expansion of the airway tubes. These respiratory movements provide one of the most powerful protective mechanisms for the lung. The protective mechanism fails in asthma so that cyclical expansion of the airway tubes can make breathing more difficult. Current belief is that protective and harmful effects of lung expansion occur by either relaxation or contraction of the muscles lining the airway tubes. Findings from this laboratory su ....Variations in lung pressures during breathing produce cyclical expansion of the airway tubes. These respiratory movements provide one of the most powerful protective mechanisms for the lung. The protective mechanism fails in asthma so that cyclical expansion of the airway tubes can make breathing more difficult. Current belief is that protective and harmful effects of lung expansion occur by either relaxation or contraction of the muscles lining the airway tubes. Findings from this laboratory suggest that the above dogma needs reconsideration. The project will utilize a novel model of the lung to enable us to determine the mechanisms producing both the protective effect, and in asthmatics the harmful effects of cyclical lung expansion. Once the part of the lung that 'fails' in this aspect of asthma has been detected then therapeutic strategies can be put in place to reverse the defect.Read moreRead less
Study Of The Functional Consequences Of Angiotensin II Induced Increases In Renal Innervation
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely imperv ....Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely impervious to preventative public health measures. While treatment of established high blood pressure can reduce the incidence of cardiovascular disease, preventing the development of hypertension in the first place is not possible at this time. A major impediment to the development of effective public health measure is our lack of knowledge of the pathological mechanisms involved, despite over 100 years of active research effort. The experiments planned in this study will probe below the surface of two important facts known about hypertension but not previously brought together - that the kidney's blood vessels and nerves are remodeled in hypertension, and that the kidney's control of the level of blood pressure must be changed in order for high blood pressure to develop in the first place. We hope that pursuit of this experimental line of enquiry will provide new clues on where to look for initiating factors in human hypertension.Read moreRead less
While it is clear that carrying excess body weight can jeopardize your health, and that losing excess weight is good for you, attaining and maintaining a healthy body weight remains an elusive goal for more than 60 % of Australian adults. There are many barriers that make permanent weight loss difficult. One of the main biological barriers to weight loss is that humans aren t designed to diet. Instead, we vehemently conserve body fat whenever food is scarce. This leads to a Famine Reaction that ....While it is clear that carrying excess body weight can jeopardize your health, and that losing excess weight is good for you, attaining and maintaining a healthy body weight remains an elusive goal for more than 60 % of Australian adults. There are many barriers that make permanent weight loss difficult. One of the main biological barriers to weight loss is that humans aren t designed to diet. Instead, we vehemently conserve body fat whenever food is scarce. This leads to a Famine Reaction that contributes to nagging hunger, lethargy, loss of libido, reduced metabolic rate, plateaus, and rebound weight gain in response to weight loss programs of any kind. In a new 3-year project funded by the National Health and Medical Research Council of Australia, molecular scientists Dr Amanda Sainsbury-Salis and Associate Professor Herbert Herzog from the Garvan Institute endeavor to get to the root of the problem. Using cutting-edge molecular, genetic, and metabolic technology, Sainsbury-Salis and Herzog aim to identify the main culprits for the Famine Reaction. They hypothesize that the natural brain molecules neuropeptide Y and the endogenous morphine-like peptide dynorphin act together as major instigators of the Famine Reaction. Therefore they will determine whether mice that are deficient in these molecules can lose more weight in response to dietary restriction than normal mice. Moreover, they will determine whether dual deficiency of neuropeptide Y and dynorphin can not only reduce the voracious appetite that occurs during caloric restriction (eg: dieting), but whether it can also speed up metabolism and promote the loss of body fat. If their hypothesis proves correct, then it s likely that novel pharmaceutical agents that block the effects of neuropeptide Y and dynorphin could dramatically increase the do-ability and long-term effectiveness of lifestyle changes for permanent weight loss.Read moreRead less
Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, litt ....Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, little is known of the response properties, structure and organization of receptors and neurones responding to, and relaying information about painful stimuli, from bone to the brain. The objectives of this project are to reveal the fundamental neural mechanisms that account for the perception of bone pain. The project will test a series of specific hypotheses in order to explain why bone pain is often poorly controlled by standard pharmacological or surgical approaches. It is expected that this study will reveal the neural mechanisms responsible for relaying sensory information, in particular, that regarding painful stimuli, from bone to the brain. It will lead to a better understanding of the mechanisms of bone pain and form the template for future studies of its treatment.Read moreRead less