We are interested to have Honours, Masters and PhD students join our team to investigate the role of PACAP and it's receptors in several models of sleep apnoea. We have exciting evidence that PACAP is at the heart of the cardiovascular consequences of sleep apnoea. This project examines fundamental mechanisms driving the cardiometabolic effects of sleep apnoea and has the potential to spearhead the development of new treatment strategies.
Cardiovascular disease (CVD) is the principal cause of death in Australia. Intriguingly 10% of CVD is now attributed to Obstructive Sleep Apnoea (OSA), a condition characterised by intermittent episodes of hypoxia during sleep, and evident in >10% of the population. Importantly, type 2 diabetes is a reciprocal risk factor for OSA. The most plausible link between OSA and CVD is that in OSA, intermittent activation of chemoreceptors leads to sympathoexcitation, that results in hypertension and diabetes.
The prevalence of OSA in patients with cardiovascular conditions is close to 50% and 60% of OSA patients are also obese. OSA and CVD are commonly associated mechanistically with obesity and the metabolic syndrome (includes hypertension, hyperglycaemia, excess abdominal adipose tissue and abnormal cholesterol levels) in general. However, this is not always the case; normal weight individuals can suffer from OSA and not all obese people have OSA.
OSA is characterised by repetitive pharyngeal collapse during sleep, with resultant oxygen desaturation (intermittent hypoxia) and sleep fragmentation. The hypoxemic/reoxygenation and hypercapnic events cause large increases in heart rate, blood pressure and frequent arousal from sleep, leading to persistently elevated sympathetic nerve activity (SNA), or sympathoexcitation. Marked sympathoexcitation commonly leads to hypertension which, in turn, causes target organ damage, resulting in atherosclerosis, renal failure, heart failure and stroke.
Metabolic effects of intermittent hypoxia occur rapidly; circulating glucose increases in conscious rats after 1hr, and in human subjects after 3hrs. These early changes could initiate triggers that promote insulin resistance and development of type 2 diabetes in human OSA conditions. Although OSA is commonly associated with obesity, rodent models of chronic intermittent hypoxia present with decreased body weight and visceral fat. Although this may seem counter-intuitive, changes that occur in the white adipose tissue are remarkably similar between animal models and the human condition. Intermittent hypoxia, and hypoxia in general, causes lipolysis, that contributes to insulin resistance. However, hypoxia within adipose tissue itself is not the sole cause of lipolysis. Rather, the sympathetic nervous system actively induces lipolysis by directly innervating adipocytes and/or causing adrenaline release which then acts on the adipose tissue. Increased circulating adrenaline, and the free fatty acids generated by lipolysis cause glycogenolysis in the liver.
PACAP is an excitatory neuropeptide found in discrete locations throughout the sympathetic chain, from the carotid body and brainstem, to sympathetic postganglionic neurons and the adrenal medulla in the periphery. PACAP binds three G-protein coupled receptors, PAC1, VPAC1 and VPAC2, to exert its effects. PAC1 is the predominant form found in the central nervous system and is specific for PACAP.
We recently showed that PACAP is necessary in the brainstem for the sympathetic response to acute intermittent hypoxia. Our exciting new data indicates that the characteristic sympathoexcitation of OSA, that is likely to cause most of the subsequent pathological metabolic changes, is mediated by intermittent release of small amounts of PACAP that act on PAC1 receptors located on sympathetic neurons in the spinal cord.
We aim to understand how PACAP drives the sympathetically-mediated increases in blood glucose and blood pressure in models of sleep apnoea.
We will determine how PACAP and its receptors drive development of the metabolic syndrome that occurs in rodent models of OSA. This will be addressed using physiological and pharmacological methods in in vivo models, as well as molecular and histochemical/anatomical and proteomic approaches. Our team has expertise in in vivo models and all techniques necessary to complete this project.
Opportunities exist for:
1. Pharmacological and optogenetic manipulation of neurons in whole system physiology preparations, including genetic knock-out models.
2. Functional anatomy using combined multiple fluorescence immunohistochemistry and in situ hybridisation techniques.
The opportunity ID for this research opportunity is 2596