A Novel Role For Proteolysis In Promoting Inner Ear Cell Injury And Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$972,818.00
Summary
Nearly 40% of hearing loss is attributable to traumatic noise exposure. This project will test a new idea that cells in the inner ear are damaged and die via noise-induced proteolysis, and investigate whether a similar mechanism operates during age-related hearing loss. It will open new avenues for therapies to preserve hearing where trauma is unavoidable, or has occurred through accident or incident.
Investigating The Role Of SERPINB6 In Cochlear Function And Deafness
Funder
National Health and Medical Research Council
Funding Amount
$570,803.00
Summary
In 2010 a novel genetic mutation was identified that causes progressive hearing loss in humans, however, it was not established why this mutation leads to the disease. We propose that the mutation renders cells of the inner ear more susceptible to death caused by noise trauma. We will investigate this in a mouse model of the human condition. This could lead to the development of therapies that prevent hearing loss.
Evolutionary Conservation Of Caspase Regulatory Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$585,215.00
Summary
Apoptosis is a highly controlled process by which metazoans eliminate unwanted and dangerous cells. Dysregulation of apoptosis can contribute to many conditions including cancer, autoimmune and degenerative diseases. To develop therapeutic reagents that promote cell death when it fails to occur, or prevent it from happening inappropriately, it is necessary to understand the mechanisms controlling apoptosis. To date, many of the important insights into mammalian cell death signalling have been in ....Apoptosis is a highly controlled process by which metazoans eliminate unwanted and dangerous cells. Dysregulation of apoptosis can contribute to many conditions including cancer, autoimmune and degenerative diseases. To develop therapeutic reagents that promote cell death when it fails to occur, or prevent it from happening inappropriately, it is necessary to understand the mechanisms controlling apoptosis. To date, many of the important insights into mammalian cell death signalling have been informed by studies of apoptotic pathways in simpler, experimentally tractable model organisms. This project will exploit biochemical approaches and powerful yeast-based tools developed by CI-A to further explore cell death pathways of the nematode Caenorhabditis elegans, and compare these with mammalian apoptosis pathways. Key findings will be verified using genetic approaches. Most apoptotic stimuli ultimately kill mammalian, insect or nematode cells by triggering activation of proteases termed caspases. However, the mechanisms by which caspase activity is regulated appear to differ somewhat between mammals and worms. We will address two general possibilities: either these animals really do differ significantly in the upstream regulation of cell death pathways, or that functional counterparts of key components have not hitherto been identified or fully characterised. Understanding the way in which mammalian apoptosis is regulated will aid in the design of diagnostic and therapeutic reagents for the many diseases in which dysregulation of apoptosis has been implicated. This project seeks to define the extent to which apoptotic regulation is conserved between mammals and nematodes. This knowledge will enable researchers to maximise the utility of nematode cell death models for the further elucidation of mammalian cell death regulatory mechanisms, and to explore how apoptosis can be manipulated for clinical benefit.Read moreRead less