This study combines sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses to determine how gut hormones regulate satiety. By utilising unique conditional and germline KO mice , this research will make highly original and internationally competitive contributions to the understanding of the regulation of satiety and energy expenditure. Knowledge as to the causes of lack of satiety will be of great benefit in the search for novel treatments for obesity.
Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
Molecular Definition Of Neural Pathways In The Embryo And Adult Mouse
Funder
National Health and Medical Research Council
Funding Amount
$401,000.00
Summary
It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate ....It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate the expression pattern of SCL in the CNS, to identify the phenotype of neural cells that express SCL in different regions of the mouse brain, and to ablate the SCL gene at different time points during life (during embryonic development, just after birth and during adulthood). These experiments will be performed in conditional transgenic mice that have unique and precisely defined genetic alteration and are generated by us specifically for our research on the SCL-gene. This genetic approach is used to define the neuroanatomical and molecular bases of SCL-function in the brain.Read moreRead less
The Role Of The NPY System In The Regulation Of Appetite And Satiety
Funder
National Health and Medical Research Council
Funding Amount
$1,088,384.00
Summary
Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this rese ....Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this research will make highly original and internationally competitive contributions to the understanding of these disorders. The results will have a significant impact on the development of novel diagnostics and potential treatments for obesity and anorexia. In addition, funding provided through this grant would not only help to find answers to these important questions but will also provide the basis for the generation of several novel mouse models. These animal models will also be beneficial tools for the wider scientific community here in Australia and worldwide. We have a proven record in the generation and comprehensive analysis of transgenic and knockout mice models making this proposal not only feasible but also highly likely to succeed and provide great new insight into extremely important health problems.Read moreRead less
Obesity is an every increasing problem worldwide, with major risks for the development of associated cardivasular and type II diabetes related disorders. This research project will determine the underlying mechanisms of how specific receptors in the brain control energy metabolism, appetite and body fat accumulation. It will also determine how peripheral factors can influence this process. The outcome of this research should identify new targets and approaches to prevent and treat obesity and th ....Obesity is an every increasing problem worldwide, with major risks for the development of associated cardivasular and type II diabetes related disorders. This research project will determine the underlying mechanisms of how specific receptors in the brain control energy metabolism, appetite and body fat accumulation. It will also determine how peripheral factors can influence this process. The outcome of this research should identify new targets and approaches to prevent and treat obesity and the associated, type 2 diabetes and cardiovascular disorders.Read moreRead less
Regulation Of Lysosomal Proteases By The Intracellular Serpin, PI-6.
Funder
National Health and Medical Research Council
Funding Amount
$152,500.00
Summary
All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell a ....All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell act as stress sensors and participate in initiating programmed cell death. In particular, it appears that degradative enzymes (proteases) released under stress from waste disposal-recycling organelles (lysosomes) can induce death. This may occur in settings such as infection or cardiovascular disease (e.g. stroke). As part of a defence mechanism to counter low level release of these lysosomal proteases, we propose that some cells produce inhibitors called serpins. In preliminary work we have shown that particular serpins do indeed inactivate a subset lysosomal proteases. We propose to study the role of these serpins in protecting cultured cells from stress and the effects of lysosomal protease release. In addition, we will use mice lacking one of these serpins to evaluate its importance in the physiological response to stresses such as bacterial and viral infection, tumor formation and stroke.Read moreRead less
C-Cbl-directed Leukaemogenesis: The Roles Of Core-Binding Factors And PI 3-kinase Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$636,199.00
Summary
Myeloid leukaemia remains a major health problem with only about one third of patients being cured. More effective treatments are therefore needed. For these treatments to be developed more knowledge is required about the genetic and biochemical changes that cause myeloid leukaemia. This project aims to increase this knowledge by studying how cancer-causing proteins are involved in the development of myeloid leukaemia and how targeting these proteins can be used to develop new treatments.
All cells have a characteristic shape (morphology), which is intrinsic to cellular function. A blood cell is designed to move in a liquid medium whereas a muscle cell is optimised for physical movement of attached bones. We are studying the mechanisms which control cell shape. We focus on the components of the cell skeleton (cytoskeleton) which are implicated in the regulation of shape. In particular, we study the actin based microfilament system. We have previously shown that two types of these ....All cells have a characteristic shape (morphology), which is intrinsic to cellular function. A blood cell is designed to move in a liquid medium whereas a muscle cell is optimised for physical movement of attached bones. We are studying the mechanisms which control cell shape. We focus on the components of the cell skeleton (cytoskeleton) which are implicated in the regulation of shape. In particular, we study the actin based microfilament system. We have previously shown that two types of these components of the cytoskeleton are able to control the structure of cells. In addition, we have found that variants of these two components (called isoforms) are used to build structures in different parts of cells. This has led us to think about the anatomy of cells and tissues in a new way. In some ways its like building a city. You create different kinds of buildings to suit their purpose. Each building uses a combination of building blocks which suit the structural demands of rooms and the overall building. In this study, we are proposing to dissect out genes, or parts of genes, which supply specific types of building blocks. To do this, we plan to change these genes in mice and then examine the impact on cell and tissue anatomy. This promises to contribute to the conversion of anatomical science and pathology from descriptive to experimental-mechanistic disciplines.Read moreRead less