Regulatory RNAs Underlying Genetic Associations With Ankylosing Spondylitis
Funder
National Health and Medical Research Council
Funding Amount
$431,201.00
Summary
Ankylosing spondylitis is a chronic inflammatory disease affecting the spine and causing back pain. The diagnosis of the disease is delayed by up to 10 years due to lack of accurate tests. We aim to identify molecular signatures of the disease that might be used to distinguish inflammatory processes typical of the disease and other causes of back pain. This would allow earlier and more accurate diagnosis of the disease and result earlier patient treatment and better health outcomes.
Nuclear Import Of The HIV-1 Pre-integration Complex: Mechanism And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The human immunodeficiency virus (HIV) has a unique feature distinguishing it from other retroviruses the ability to replicate in non-dividing cells such as in macrophage-microglia cells which are among the prime target cells for virus infection. The viral genome needs to be integrated into the host cell chromosome in order to infect cells productively. The host cell s genome is not normally accessible because it is located inside the nucleus, separated from the rest of the cell by the barrier o ....The human immunodeficiency virus (HIV) has a unique feature distinguishing it from other retroviruses the ability to replicate in non-dividing cells such as in macrophage-microglia cells which are among the prime target cells for virus infection. The viral genome needs to be integrated into the host cell chromosome in order to infect cells productively. The host cell s genome is not normally accessible because it is located inside the nucleus, separated from the rest of the cell by the barrier of the nuclear envelope (NE). However, HIV has found a way to transport its genome to the nucleus in a complex together with other viral-cellular proteins, the pre-integration complex (PIC), through the intact NE of non-dividing cells. This is a crucial step of viral infection and if blocked could prevent the establishment and spread of HIV infection. Thus far it is unclear how the large HIV PIC accesses the nucleus and which viral and cellular proteins are essential for the navigation of the PIC through the NE and into the nucleus. Using fluorescent labels on the key components of the HIV PIC including the DNA in combination with confocal laser scanning microscopy and a novel optical single-transporter recording technique, we will be able to visualize the PIC on its way through the NE for the first time. Mutational analyses will further identify the key residues of viral proteins and the cellular nuclear transport machinery utilized during the transport. The results of this study will literally provide a clear picture of nuclear import of the HIV PIC. The future aim of elucidating this essential step in HIV replication is to identify new targets for anti-retroviral drug interventions that may be less prone to side effects and development of resistance than the currently available drug regimens.Read moreRead less
The Leucine Rich Repeat Kinase 1 And 2 Genes Are Modulators Of Alternative Splicing - Implication For Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$583,809.00
Summary
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two common causes of dementia and neurodegeneration. Through positional cloning, we have identified the leucine rich repeat kinase (LRRK1) 1 gene as a modulator of alternative splicing. We have subsequently shown that its homologue, LRRK2 has a similar biological activity. We propose to study the the genetic and biochemical role of LRRK1 and LRRK2 in neurodegeneration in terms of its effect in splicing.
Cloning Of Human NK Cells And Macrophages Carbohydrate Receptors
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Lymphocytes, also known as white blood cells, are important for the well being of all individuals as these are the cells which fight infection by microorganisms. The lymphocyte gets its information about enviroment and communicates with other cells using molecules on the cell surface. We are examining a group of molecules found on the surface of different lymphocytes which bind different sugars, and also to characterised new cell surface molecules that interact with carbohydrates. These studies ....Lymphocytes, also known as white blood cells, are important for the well being of all individuals as these are the cells which fight infection by microorganisms. The lymphocyte gets its information about enviroment and communicates with other cells using molecules on the cell surface. We are examining a group of molecules found on the surface of different lymphocytes which bind different sugars, and also to characterised new cell surface molecules that interact with carbohydrates. These studies will examine the structure of the the molecules that interact with with sugars, in order to understand how these give messages to the lymphocyte to trigger various functions that these cell perform in the immune response. We will isolate the genes for these and study their function in greater detail. The cell surface carbohydrate receptors represents several different families of molecules, it is highly likely that these have important roles in the immune response. The potential significance of studying these lymphocyte cell surface molecules is in defining the functional properties of these molecules, the results of which will give us novel insights into the molecular mechanisms involved in the generation of immune responses, the mechanism of immuno deficiency and autoimmunity.Read moreRead less
Molecular Characterisation Of Lipid Droplet Function
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Fat is stored inside cells in spherical structures called lipid droplets. The accumulation of fat within lipid droplets underlies obesity. This project aims to understand how fat is stored within lipid droplets and how it is released when energy is required. In particular, we will look at two types of protein which move to lipid droplets under certain energy conditions and attempt to unravel how these proteins control fat storage and release. The first protein we will study, caveolin, normally a ....Fat is stored inside cells in spherical structures called lipid droplets. The accumulation of fat within lipid droplets underlies obesity. This project aims to understand how fat is stored within lipid droplets and how it is released when energy is required. In particular, we will look at two types of protein which move to lipid droplets under certain energy conditions and attempt to unravel how these proteins control fat storage and release. The first protein we will study, caveolin, normally associates with regions of the cell surface but moves to lipid droplets when cells are fed lipids. Mice which lack this protein eat more food but remain leaner than normal mice. Understanding how caveolin moves to lipid droplets and how it controls fat accumulation will therefore provide new insights into obesity and conditions associated with obesity, such as diabetes. The second protein to be studied, Rab18, is a member of a protein family which controls membrane movement within cells. Rab18 moves to lipid droplets when lipid release is stimulated. Therefore studies of Rab18 can provide new insights into the way lipids are released from fat tissue under conditions of starvation. The project will provide fundamental new insights into the basic mechanisms by which we store energy and the energy imbalances which cause obesity and related diseases.Read moreRead less
Biological Characterisation Of The Opiod Receptor Sigma 1 Gene In The Frontotemporal Dementia And Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,211.00
Summary
Frontotemporal dementia (FTD) and motor neuron disease (MND) are the two common causes of dementia and neurodegeneration. We have identified a new genes that causes familial FTD and MND in pedigrees affected with dementia and-or MND.This project will study the expression and function of this new FTD-MND gene to determine its role in the aetiology and pathology of this complex of neurodegenerative disorders.
Dissecting The Pseudoexfoliation Syndrome With Complementary Genetic, Proteomic And Biophysical Strategies
Funder
National Health and Medical Research Council
Funding Amount
$490,352.00
Summary
Pseudoexfoliation syndrome (PEX) is an eye condition in which flaky material deposits in the eye, greatly increasing the risk of cataract and glaucoma which can lead to blindness. PEX is also associated with heart disease, strokes and aneurysms. Cataract surgery in PEX patients has a higher rate of complications. In this project we will determine the nature of PEX material and why it forms. This knowlege will facilitate better diagnosis and treatment of PEX preventing associated blindness.