A NEW LOOK AT THE ROLE(S) OF GLYCOGEN AND SUGAR PHOSPHATES IN SKELETAL MUSCLE CONTRACTILITY
Funder
National Health and Medical Research Council
Funding Amount
$193,224.00
Summary
According to textbooks, glycogen in skeletal muscle is a homogenous molecular species whose sole role in muscle contraction is that of a carbohydrate-energy store. Likewise, sugar phosphates, such as glucose1-phosphate (G1-P), glucose 6-phosphate (G6-P), fructose 6-phosphate (F6-P) and fructose 1,6-bisphosphate (F1,6-bP) are generally presented as negatively charged compounds that act only as substrates-products of intermediary reactions in sugar degradation pathways. However, there is now compe ....According to textbooks, glycogen in skeletal muscle is a homogenous molecular species whose sole role in muscle contraction is that of a carbohydrate-energy store. Likewise, sugar phosphates, such as glucose1-phosphate (G1-P), glucose 6-phosphate (G6-P), fructose 6-phosphate (F6-P) and fructose 1,6-bisphosphate (F1,6-bP) are generally presented as negatively charged compounds that act only as substrates-products of intermediary reactions in sugar degradation pathways. However, there is now compelling evidence that (i) glycogen depletion impairs muscle contractility even when there is no shortage of cellular energy, (ii) there are two molecular forms of glycogen, and (iii) sugar phosphates can act as potent modifiers of functional domains in muscle proteins. This project addresses a number of novel questions regarding the role (s) of glycogen and sugar phosphates in muscle contractility and the cellular mechanisms involved. The knowledge produced will further our understanding of the correlation between Excitation-Contraction coupling and different intracellular glycogen pools, and of the molecular basis of prolonged effects of sugar phosphates on the contractile machinery. Furthermore, this work should also generate valuable insights into complex physiological (e.g. fatigue and aging) and pathological (e.g. atherosclerosis, metabolic myopathies) conditions which are still poorly understood.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.