Is FGF21 the master regulator of protein intake? The project plans to bring together two major, rapidly growing disciplines – nutritional geometry and metabolic signalling – to address a topic of fundamental biological significance: the regulation of protein intake. A specific capacity to regulate protein intake has been shown for organisms spanning slime moulds to humans, yet the controlling mechanisms remain elusive. The project aims to test the hypothesis that fibroblast growth factor 21, rel ....Is FGF21 the master regulator of protein intake? The project plans to bring together two major, rapidly growing disciplines – nutritional geometry and metabolic signalling – to address a topic of fundamental biological significance: the regulation of protein intake. A specific capacity to regulate protein intake has been shown for organisms spanning slime moulds to humans, yet the controlling mechanisms remain elusive. The project aims to test the hypothesis that fibroblast growth factor 21, released from the liver under low protein nutrition, is a master regulator of protein intake. Understanding the mechanisms of protein appetite may have implications for organismal biology, understanding social interactions, the structure of food webs and the health and welfare of food and companion animals and humans.Read moreRead less
Anti-ageing role for relaxin in blood vessels. Arteries stiffen with age. This is due to increased arterial smooth muscle tone and alterations in the extracellular matrix. In a sense, the artery undergoes ?fibrosis? with aging. In light of the anti-fibrotic attributes of the peptide hormone relaxin observed in other tissues, this collaborative project will investigate the potential role for relaxin in opposing arterial ?fibrosis? associated with aging. We will test the hypothesis that a reductio ....Anti-ageing role for relaxin in blood vessels. Arteries stiffen with age. This is due to increased arterial smooth muscle tone and alterations in the extracellular matrix. In a sense, the artery undergoes ?fibrosis? with aging. In light of the anti-fibrotic attributes of the peptide hormone relaxin observed in other tissues, this collaborative project will investigate the potential role for relaxin in opposing arterial ?fibrosis? associated with aging. We will test the hypothesis that a reduction in arterial relaxin expression in older animals is a major cause of arterial stiffening. Further studies will investigate the mechanisms by which relaxin administration can alleviate this phenomenon.Read moreRead less
Relaxin action in the heart, kidney, lung and uterus: understanding fibrosis. Relaxin is a peptide hormone associated with pregnancy. We have recently generated a relaxin gene knockout mouse and exciting preliminary data show that without relaxin, non-pregnant mice develop signs of fibrosis in the heart, lung and uterus. Combining our expertise in molecular biology, pharmacology and physiology, the overall objective of this project is to investigate the functions and mechanisms of relaxin action ....Relaxin action in the heart, kidney, lung and uterus: understanding fibrosis. Relaxin is a peptide hormone associated with pregnancy. We have recently generated a relaxin gene knockout mouse and exciting preliminary data show that without relaxin, non-pregnant mice develop signs of fibrosis in the heart, lung and uterus. Combining our expertise in molecular biology, pharmacology and physiology, the overall objective of this project is to investigate the functions and mechanisms of relaxin action in these organs. Our findings will provide important basic information on relaxin physiology and enable us to implement a long-term partnership with Connetics to understand how relaxin regulates collagen production and/or the development of fibrosis.Read moreRead less
Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard ....Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard tail), to describe the regrowth process and determine the abundance, location, functional properties and molecular control of the new lymphatics. Furthermore, if reptilian lymphatic growth factors can promote lymphangiogenesis in mammals, we can design novel therapeutic approaches using reptilian ligands to promote lymphangiogenesis in lymphoedematous human tissues.Read moreRead less
Epigenetic Regulation of Fetal and Placental Development. Perturbations of the environment of the early embryo can alter fetal and placental growth. The mechanisms by which the early environment alters development of the fetal adrenal-placental axis are unknown. This axis coordinates fetal growth and development to ensure a successful transition from intra- to extrauterine life. We propose a novel role for the epigenetic regulation of imprinted genes in the activation of the fetal adrenal and in ....Epigenetic Regulation of Fetal and Placental Development. Perturbations of the environment of the early embryo can alter fetal and placental growth. The mechanisms by which the early environment alters development of the fetal adrenal-placental axis are unknown. This axis coordinates fetal growth and development to ensure a successful transition from intra- to extrauterine life. We propose a novel role for the epigenetic regulation of imprinted genes in the activation of the fetal adrenal and in placental growth and differentiation. This proposal extends the 'genetic conflict' hypothesis of the role of imprinted genes beyond its current focus on the regulation of fetal nutrient supply and demand.Read moreRead less
The Immunoregulatory Role of the Endogenous Cannabinoid Anandamide. Anandamides are naturally occurring fatty acids that act at the cannabinoid receptor expressed in the brain and periphery. A new proposal by our research group challenges traditional models of the disease process by suggesting that the anandamide system is an important imunoregulatory system that can be targeted by invading pathogens. We propose that disruption to the anandamide system, by bacteria or viruses acting at the rece ....The Immunoregulatory Role of the Endogenous Cannabinoid Anandamide. Anandamides are naturally occurring fatty acids that act at the cannabinoid receptor expressed in the brain and periphery. A new proposal by our research group challenges traditional models of the disease process by suggesting that the anandamide system is an important imunoregulatory system that can be targeted by invading pathogens. We propose that disruption to the anandamide system, by bacteria or viruses acting at the receptor to block immunological responses, contributes to chronic illness states. At this point we have good evidence that anandamides are immunoregulators, however, we have very little knowledge of their precise physiological role. The aim of this research is to begin to characterise the immunoregulatory role of the anandamide system. This project will provide a comprehensive understanding of this endogenous control system, the immunological properties of which have not previously been described. The outcome of this research may lead to the identification of new avenues for the development of pharmaceutical interventions that can target this system.Read moreRead less
Evolution of sound localisation in vertebrates: head size, sound frequency and neural phase-locking. Hearing is our most important sense for interpersonal communication, yet we have a fragmentary understanding of the basic mechanisms involved in normal hearing. This project addresses the question of how sound location is represented in the brain through the processing of minute time difference with which sounds reach the two ears. The outcome will ultimately enable us to infer how the human brai ....Evolution of sound localisation in vertebrates: head size, sound frequency and neural phase-locking. Hearing is our most important sense for interpersonal communication, yet we have a fragmentary understanding of the basic mechanisms involved in normal hearing. This project addresses the question of how sound location is represented in the brain through the processing of minute time difference with which sounds reach the two ears. The outcome will ultimately enable us to infer how the human brain localises sound, with practical applications for improved virtual auditory realities and hearing aids.Read moreRead less
Relaxin: molecular mechanisms of action in the reversal of fibrosis. Defects in relaxin and relaxin receptors are increasingly implicated as a cause of fibrosis which is associated with many disease processes. This study will examine the molecular mechanisms linking relaxin and fibrosis and will determine whether relaxin can be used to reverse the condition.
Does muscle contribute to the maintenance of vitamin D status in winter? This project aims to test the mechanism by which vitamin D status is maintained in winter when input is low. The long half-life in blood of the vitamin D metabolite, 25-hydroxyvitamin D [25(OH)D], maintains an adequate vitamin D status over winter, when sunlight, which produces vitamin D in skin, is reduced. From preliminary data in sheep and mice, this project proposes that skeletal muscle, not fat, stores vitamin D. This ....Does muscle contribute to the maintenance of vitamin D status in winter? This project aims to test the mechanism by which vitamin D status is maintained in winter when input is low. The long half-life in blood of the vitamin D metabolite, 25-hydroxyvitamin D [25(OH)D], maintains an adequate vitamin D status over winter, when sunlight, which produces vitamin D in skin, is reduced. From preliminary data in sheep and mice, this project proposes that skeletal muscle, not fat, stores vitamin D. This project will test this hypothesis in sheep, cultured muscle cells and in transgenic mice. The project will confirm whether the processes identified in skeletal muscle contribute to the maintenance of vitamin D status, and identify ways of enhancing this process.Read moreRead less
Saving your skin: physiology of immune regulation in mammalian lymph nodes. The overall aim of this proposal is to understand the mechanisms through which a rare population of regulatory cells maintains skin integrity. Despite their importance, little is known about the regulatory pathways these cells utilise. Previous work from the team has described an innovative technique to enrich these cells for in-depth study and demonstrated their potent regulatory capacity in vivo. This project will enha ....Saving your skin: physiology of immune regulation in mammalian lymph nodes. The overall aim of this proposal is to understand the mechanisms through which a rare population of regulatory cells maintains skin integrity. Despite their importance, little is known about the regulatory pathways these cells utilise. Previous work from the team has described an innovative technique to enrich these cells for in-depth study and demonstrated their potent regulatory capacity in vivo. This project will enhance our understanding of these cells and uncover their mechanisms of action. The outcomes of this work will therefore provide fundamental new knowledge of skin physiology, and lead to novel insights regarding how healthy skin, which is essential for the very survival and function of a living organism, may be maintained.Read moreRead less