Structural And Functional Studies On RNA Nuclear Retention Mediated By Paraspeckles: A Novel Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$290,978.00
Summary
Dynamic interactions between proteins and nucleic acids are essential process in gene regulation, where aberrant regulation leads to various diseases including cancers. The project aims to examine the interactions between paraspeckle proteins and nucleic acid molecules via determination of the structures of protein-nucleic acid complexes at the atomic level. The results will provide a better understanding of a recently discovered gene regulation mechanism and a basis for new gene therapy.
Great advances have been made in pharmaceutical design and discovery over the last 50 years. While drugs have traditionally been discovered using random screening of natural product libraries and chemical databases, new technologies in protein chemistry, structural and molecular biology have been adopted in efforts to speed the drug design process and increase its hit rate. In addition, our rapidly increasing knowledge of the molecular causes of many diseases provides us with many opportunities ....Great advances have been made in pharmaceutical design and discovery over the last 50 years. While drugs have traditionally been discovered using random screening of natural product libraries and chemical databases, new technologies in protein chemistry, structural and molecular biology have been adopted in efforts to speed the drug design process and increase its hit rate. In addition, our rapidly increasing knowledge of the molecular causes of many diseases provides us with many opportunities to develop therapeutics directed towards known molecular targets. Nevertheless, despite these advances, problems such as drug resistance and toxic side effects that compromise drug efficacy make it clear that there is a need for new classes of drugs with different modes of action. Because of their favourable properties, small-molecule drugs comprise by far the largest class of currently available therapeutics. However, in many cases, a drug derived from a protein may be preferable. The development of protein-based drugs is a youthful and rapidly expanding area of biotechnology, but to date, most studies have focused on targeting pathological events that occur on the outside of cells. We propose to use a combination of methods from molecular and structural biology, together with recently developed high-throughput screening techniques, to develop a generic protein drug scaffold that can be used as a template to develop therapeutics against a wide range of inappropriate interactions that may occur between molecules within cells.Read moreRead less
The Structural Basis For Amyloid Formation By Human Apolipoproteins
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies (e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different types of amyloid. The current wide publicity given to bovine spong ....Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies (e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different types of amyloid. The current wide publicity given to bovine spongiform encephalopathy (BSE) disease and the potential impact on human health highlights the importance of developing strategies for treating these conditions. The prevalence of apolipoproteins in atherosclerotic amyloid deposits and senile plaques suggests a general propensity for human apolipoproteins to form pathogenic amyloid fibrils. Our recent observations that lipid-free human apolipoprotein C-II (apoC-II) forms ribbon-like fibrils in vitro provides an experimental system to explore this phenomenon. We propose to determine the structural requirements for the formation of amyloid fibrils human apoC-II and whether lipid-free human apolipoproteins form mixed-amyloid fibrils. Future strategies for treatment require better information on amyloid structure, the potential for mixed amyloid formation and the role of in vivo factors such as lipids and macromolecular crowding in regulating amyloid growth.Read moreRead less
The Role Of Huntingtin Misfolding And Oligomerization In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$474,329.00
Summary
Mutations in the huntingtin gene cause Huntington's disease by making the gene product aggregate together into non-normal and different sized polymers. However, it is not understood how this process causes cells to die, largely because we don't understand how the abnormal forms accumulate in cells over time. We will examine where in cells the abnormal shapes accumulate and how they cause toxicity. This research will identify critically-needed therapeutic targets against Huntington's disease.
Structural Basis For Restraint And Activation Of Pro-apoptotic Bax And Bak
Funder
National Health and Medical Research Council
Funding Amount
$246,478.00
Summary
The aim of this project is to understand how cell death is controlled. Defects in the cell death machinery occur in many cancers, making that machinery an attractive target for cancer therapeutics. My experiments will yield atomic resolution pictures of the functional machinery, illustrating for the first time how the molecular brakes are applied to prevent cells dying. Understanding these structures will aid the discovery of drugs that can activate the cell death machinery in cancer cells.
Probing The Control And Action Of CLIC1/NCC27, An Unusual Chloride Ion Channel, By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$271,320.00
Summary
Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structure of this class of channel in the soluble state. In this project, we will determine: how the protein makes the transition into the membrane state; which factors control this transition; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm for other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.Read moreRead less
Chemical Aided Phospoproteome Sequencing With Mass Spectrometry
Funder
National Health and Medical Research Council
Funding Amount
$141,000.00
Summary
Essentially all of the body's functions from muscle contraction, energy expenditure through to appetite are controlled by a complex molecular communications system. One of the key elements involves the modification of proteins to alter their properties by adding and removing phosphate. By analysing this process in response to diet and exercise we will obtain a greater understanding of their health benefits and understand how type 2 diabetes and obesity develop at the molecular level.
The Role Of Presenilin In Metal Homeostasis And Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$86,335.00
Summary
Presenilin, a protein involved in Alzheimer’s disease (AD), may regulate copper and zinc levels. Copper and zinc are essential nutrients however a deficiency or excess can cause disease. Promising metal-altering AD drugs, are in various stages of clinical trial. I aim to characterize the interaction of Presenilin and metals using both mouse and cultured human cell models that are deficient in Presenilin. Understanding this interaction should lead to better drug design and treatment of AD.