Neurons And Neurotransmitters That Control Phasic Laryngeal Motoneuron Activity
Funder
National Health and Medical Research Council
Funding Amount
$278,736.00
Summary
Opening and closing of the vocal cords with breathing is an automatic function that is present before birth and is essential for life. Opening the vocal cords allows inspired air to enter the lungs and closure serves to protect the lungs from food and drink. Failure of coordination is associated with a range of life-threatening airway disorders, particularly in newborns. Nerves in the brain and the chemicals they release transmit the rhythm of breathing to the nerves that control the vocal cords ....Opening and closing of the vocal cords with breathing is an automatic function that is present before birth and is essential for life. Opening the vocal cords allows inspired air to enter the lungs and closure serves to protect the lungs from food and drink. Failure of coordination is associated with a range of life-threatening airway disorders, particularly in newborns. Nerves in the brain and the chemicals they release transmit the rhythm of breathing to the nerves that control the vocal cords. However, the specific neurons and chemicals involved are not known. This information is crucial in understanding the chemical disorder in the brain responsible for the loss of coordination between breathing and vocal cord activity, and in formulating strategies to treat these conditions using drugs that correct the chemical disorder. By way of example, we have used our animal studies to develop the first ever drug trial to treat children with congenital vocal cord paralysis, whose vocal cords fail to open with inspiration and require a tracheostomy. We have selected a drug that corrects the proposed disorder of brain chemistry responsible for this condition. This approach will serve as a template for the management of a variety of other life-threatening airway disorders in newborns using drugs that act on the brain. We will now carry out further experiments to identify the nerves and their chemicals that control the motoneurons that drive the vocal cords. The key experiment involves recording from inside an individual vocal cord motoneuron in the brain while simultaneously applying a range of chemicals to its external surface. By recording the response of the nerve, we can determine which chemicals control its activity. Using our knowledge of the pattern of chemicals released by respiratory neurons, we will identify neurons for further study, and establish chemical and anatomical relationships between the respiratory nerve and the vocal cord nerve.Read moreRead less
Regulation Of Extraocular Myosins In Craniofacial Muscles
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Muscles which move the eyeball are highly complex and contain a special motor protein which enables them to contract with the highest speed of all muscles in the body. This protein is found also in muscles of the throat which open and close the airway during coughing, sneezing and swallowing. These muscles also make many other types of motor proteins, giving them a wide spectrum of properties. The functional advantage of having very fast muscles to move the eyes, and protect the airway by preven ....Muscles which move the eyeball are highly complex and contain a special motor protein which enables them to contract with the highest speed of all muscles in the body. This protein is found also in muscles of the throat which open and close the airway during coughing, sneezing and swallowing. These muscles also make many other types of motor proteins, giving them a wide spectrum of properties. The functional advantage of having very fast muscles to move the eyes, and protect the airway by preventing foreign bodies from entering the lungs, is obvious, but how the synthesis of this motor protein is restricted to these muscles is intriguing. Studies in limb muscles have established the principle that the type of motor protein in a muscle is determined by both the type of muscle cells and the type of innervation. Nerves can change the motor proteins in response to the pattern of use imposed by the brain via electrical impulses along its nerve supply. It is known that frequency of nerve impulses to eye muscles are exceptionally high. This project will use several approaches to test the hypothesis that the nerve impulse pattern delivered to these special muscles is involved in the regulation of this motor protein. In one approach, these muscles in rat will be subject to long-term paralysis by cutting their nerve or by the use of botulinum toxin to see if the motor protein is abolished or reduced. In another, the nerve to throat muscles which make this protein will be redirected to another throat muscle which does not normally make this motor protein. These experiments are expected to support the notion that eye and throat muscles are different from all other muscles in the body, and that the normal neural activity from nerves innervating these special muscles is necessary for inducing the synthesis of their motor proteins. These results will greatly help us understand how eye and throat muscles acquire their unique characteristics.Read moreRead less
Exertional Dyspnoea With Increased Filling Pressure - Mechanisms And Treatment Strategies
Funder
National Health and Medical Research Council
Funding Amount
$387,793.00
Summary
Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and theref ....Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and therefore, outcome) than with late stage disease. Current treatment strategies are expensive and because they are directed at end-organ damage (heart failure, heart attacks etc), rather ineffective. This multispecialty, multidisciplinary group will undertake a series of unique studies aimed at identifying early cardiovascular disease. The strategy will involve detection of abnormal filling behaviour at stress echocardiography, with randomization into longterm and short-term trials to examine various therapeutic strategies. Sensitive new cardiovascular imaging techniques will be used to detect preclinical abnormalities in the structure and function of the heart and vasculature, facilitating a mechanistic understanding of the process of increasing filling pressure with exercise.Read moreRead less
The Effect Of CPAP On Erectile And Endothelial Dysfunction In Impotent Men With Obstructive Sleep Apnea
Funder
National Health and Medical Research Council
Funding Amount
$609,559.00
Summary
Erectile dysfunction is common in men with obstructive sleep apnea, due to vascular damage, which leads to heart attack. CPAP is the preferred treatment for patients with OSA because of its well-proven ability to decrease sleepiness and improve blood pressure control. This study will establish if CPAP can also improve erectile and vascular endothelial dysfunction. These results will shed light on the mechanisms that underpin the relationship between OSA and Erectile Dysfunction.
Efficacy And Mechanisms Of Exercise Training In Diastolic Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$385,250.00
Summary
Heart failure is modern epidemic which presents a significant public health burden, due to a high mortality, frequent hospital admissions and impaired functional capacity. Although the typical heart failure patient presents with a reduced contractile function, many patients have typical heart failure symptoms but with normal contraction. The problem in these patients seems to relate to the heart's ability to fill with blood, and this entity is known as diastolic heart failure (DHF). This syndrom ....Heart failure is modern epidemic which presents a significant public health burden, due to a high mortality, frequent hospital admissions and impaired functional capacity. Although the typical heart failure patient presents with a reduced contractile function, many patients have typical heart failure symptoms but with normal contraction. The problem in these patients seems to relate to the heart's ability to fill with blood, and this entity is known as diastolic heart failure (DHF). This syndrome is most frequently due to ischemic or hypertensive heart disease, and most commonly occurs in the elderly. The optimal management of DHF is not well defined, although some drug trials are currently in progress. A number of studies have shown exercise training to improve functional capacity by 15-20% in typical heart failure. However, training has not so far been trialled in DHF. In this multicenter, multi-disciplinary study, we will study a training and control group to determine whether exercise capacity and DHF symptoms are responsive to exercise training. This work will teach us about the optimum exercise prescription, in terms of the duration and nature of training, as well as the safety and effectiveness of exercise training. By using a number of sensitive measurements of heart and vessel function (in which our group has special expertise), we will identify whether exercise training exerts its effect through improvement in vascular function and myocardial properties. If successful, the clinical implications of this study are that; 1. Exercise training will be adopted to improve functional capacity and symptoms of DHF 2. The merits of aerobic and strength training will be identified in DHF 3. Abnormal blood vessel function will be identified as a major and reversible contributor to DHFRead moreRead less
Understanding Local And Regional Determinants Of EDHF And NO Dysfunction In Resistance Arteries In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$771,295.00
Summary
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating effects of small artery disease.
Transdermal Testosterone Therapy: A Potential Treatment For Selective Serotonin Reuptake Inhibitor (SSRI)-associated Sexual Dysfunction In Women
Funder
National Health and Medical Research Council
Funding Amount
$241,351.00
Summary
Female sexual dysfunction (FSD) is frequently reported with selective serotonin reuptake inhibitor (SSRI) therapy and venlafaxine, these being the most common antidepressants used by Australian women. We have shown that testosterone therapy significantly improves sexual function in women with FSD. However SSRI-users have been excluded from these past studies. The aim of this study is to assess the efficacy of transdermal testosterone therapy for treatment of sexual dysfunction associated with SS ....Female sexual dysfunction (FSD) is frequently reported with selective serotonin reuptake inhibitor (SSRI) therapy and venlafaxine, these being the most common antidepressants used by Australian women. We have shown that testosterone therapy significantly improves sexual function in women with FSD. However SSRI-users have been excluded from these past studies. The aim of this study is to assess the efficacy of transdermal testosterone therapy for treatment of sexual dysfunction associated with SSRI therapy.Read moreRead less
Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less