Inclusion Body Proteins And Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$389,164.00
Summary
Parkinson's disease affects 1% of people aged over 50, and a related disorder, Dementia with Lewy bodies, causes dementia in elderly patients. These diseases are characterised by inclusion bodies (Lewy bodies) in a sub population of nerve cells. Multiple system atrophy, another adult-onset neurodegenerative disorder, is also characterised by inclusion bodies (glial inclusions). Inclusions may interfere with cellular function, contributing to the process of brain degeneration. The inclusion bodie ....Parkinson's disease affects 1% of people aged over 50, and a related disorder, Dementia with Lewy bodies, causes dementia in elderly patients. These diseases are characterised by inclusion bodies (Lewy bodies) in a sub population of nerve cells. Multiple system atrophy, another adult-onset neurodegenerative disorder, is also characterised by inclusion bodies (glial inclusions). Inclusions may interfere with cellular function, contributing to the process of brain degeneration. The inclusion bodies are precipitations of proteins and other cellular chemicals. In the last 10 years, in a search for the underlying cause of these neurodegenerative disorders, there has been an intensive research effort to identify the proteins precipitated in the inclusion bodies. The present project adopts a new strategy and aims to identify the precipitated proteins in the inclusion bodies in brains of people dying with Parkinson's disease, Dementia with Lewy bodies and Multiple system atrophy. We intend to isolate the Lewy bodies and the glial inclusions from fresh brain tissue of patients dying with relevant diseases. Throughout the various steps in the isolation process, the location of the inclusion bodies will be checked with a special antibody to a particular protein (alpha synuclein) which we and others have already discovered to be present in all inclusion bodies. Proteins will then be identified using electrophoresis and amino acid sequencing. With the identification of these proteins, their role in neurodegeneration in these diseases can be examined using multiple biomedical approaches. These proteins will be important candidates for developing novel diagnostic reagents, screening for gene mutations in patients, or as the target of therapeutic intervention in these diseases.Read moreRead less
Role Of Hsp40 And Hsp70 In Huntingtin Misfolding, Oligomerization And Inclusion Assembly
Funder
National Health and Medical Research Council
Funding Amount
$590,103.00
Summary
Huntington disease results from a mutation that causes the Htt protein to become abnormally sticky and form toxic clusters in neurons. Cells have natural defences to clustering with proteins called chaperones, which are exciting therapeutic targets. This project will examine how chaperones defend against toxic Htt clustering with cutting-edge imaging technologies. The knowledge gained will aid in designing therapeutic strategies that stimulate the defence processes and suppress the clusters.
Developing Novel Molecules That Target Hormone Receptors As An Alternative Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$459,867.00
Summary
A promising class of cancer drugs target heat shock protein 90 (Hsp90) and prevent Hsp90 from maintaining its ~100 proteins involved in cell growth. However, all current Hsp90 chemotherapeutics non-selectively target proteins maintained by Hsp90, and induce a cell rescue mechanism involving Hsp70. We describe the development of a novel molecule that will selectively control cell growth and prevent cell rescue via a unique Hsp90 regulated mechanism.
Understanding Age-related Protein Aggregation. The Mechanism Of Cataract And Its Prevention
Funder
National Health and Medical Research Council
Funding Amount
$709,333.00
Summary
Cataract arises from clouding of the eye lens due to the aggregation of crystallin proteins whose high concentration and close packing facilitate lens transparency. This proposal will investigate crystallin structure and interactions to understand the reasons for cataract formation and its prevention via the design of aggregation inhibitors. The results will facilitate the development of drugs to prevent cataract and other related protein aggregation diseases, e.g. Alzheimer’s and Parkinson’s.
Directed Molecular Evolution Of G Protein-coupled Receptors For Stable And Functional Expression In Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$383,479.00
Summary
Approximately half of all prescription drugs on the market act on G protein coupled receptors (GPCRs). The mechanisms underlying GPCR function are mainly unknown due to a lack of structural information. No solved structures exist for any of the estimated 800 human GPCRs, making it difficult to design new drugs. By applying advanced protein engineering techniques I aim to produce human GPCRs in bacteria to ultimately acquire structural information, which will enable novel drug development.
Disrupting Mucin-mucin Interactions To Treat Respiratory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$480,531.00
Summary
Diseases like asthma, emphysema and cystic fibrosis all feature the overproduction of mucus in the lungs that make it very difficult for patients to breathe and increases their susceptibility to infections. Few therapies are available for thinning this mucus, which is made thick by a network of linkages between proteins. We are studying these linkages and developing methods to break them up. This research could yield new mucus-thinning drugs to treat lung diseases.
Mechanisms Regulating Mitochondrial Outer Membrane Permeabilisation During Programmed Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$306,562.00
Summary
Apoptosis is a form of cell suicide that is vital in human development and health by removing damaged or unwanted cells in a regulated manner. Disturbances in this pathway are known to be the cause of cancers and other diseases. This research will investigate how the pivotal step in cell death, termed mitochondrial outer membrane permeabilisation (MOMP) is regulated.
Peptide Toxins From Animal Venoms Specifically Targeting Voltage-gated Sodium Channels As Novel Analgesics And Pesticides
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
This project aims to understand how certain animal toxins that cause analgesic and pesticidal effects in model animals interact with biological ion channels in atomistic detail using computational techniques. By understanding the detailed molecular interactions involved in the binding of the toxins to channels, toxin variants with improved potency and specificity may be designed as promising templates for novel analgesics and pesticides.
Alzheimer's, Huntington's and Parkinson's diseases involve the formation of protein aggregates, termed amyloid. The formation of amyloid leads to cell death and neurodegeneration. The most important cellular events perturbed by the formation of amyloid aggregates are unclear. Recent evidence suggests that sterols (including cholesterol) have an important role in cellular toxicity. This study will examine the molecular basis for this, enhancing our understanding of the amyloid diseases and could ....Alzheimer's, Huntington's and Parkinson's diseases involve the formation of protein aggregates, termed amyloid. The formation of amyloid leads to cell death and neurodegeneration. The most important cellular events perturbed by the formation of amyloid aggregates are unclear. Recent evidence suggests that sterols (including cholesterol) have an important role in cellular toxicity. This study will examine the molecular basis for this, enhancing our understanding of the amyloid diseases and could suggest novel therapeutic avenues.Read moreRead less