Mature red cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functional cells. We will determine the role of several molecules that interact with Lyn including Cbp, Liar and LACM, towards apects of red blood cell development.
Roles Of Ndfip1 And Ndfip2 As Adaptors For The Nedd4 Family Of Ubiquitin Ligases
Funder
National Health and Medical Research Council
Funding Amount
$656,395.00
Summary
Part of this proposal is to understand how the body controls iron uptake through one of the iron transporters (DMT1). We will also study how proteins called Ndfip1 and Ndfip2 that regulate DMT1, also control other cellular processes, such as protection against brain damage following trauma. The results from this study should ultimately contribute to the development of therapies for certain human pathologies.
Recent evidence suggests that the Siah proteins are involved in sensing low oxygen levels in cells, and subsequently activating processes to help the cell survive under these conditions. Low oxygen conditions occur in cancer and sites of inflammation, suggesting that inhibiting Siah may improve patient outcomes in diseases such as cancer and arthritis. We aim to perform a high throughput screen for drugs that inhibit Siah protein function and to test these in cancer cells.
Structural Characterisation Of SNARE Protein Complexes Involved In Insulin-regulated Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
Insulin-regulated glucose transportation is defective in type 2 diabetes, a disease that is a major health problem worldwide and in some cases can lead to death. The aim of this work is to investigate the molecular structure and function of proteins critical to the transportation and delivery of glucose to muscle and fat cells, which will lead to the validation of new therapeutic targets and the development of new treatments for diabetes.
Defining The Role And Contribution Of Cdc37 To Signal Transduction And Tumourigenesis By Src-family Kinases
Funder
National Health and Medical Research Council
Funding Amount
$411,430.00
Summary
Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade ....Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade of signaling networks that regulate the activity of the cell. Significantly though, the inappropriate activation of Src-family kinases has been implicated in the development of cancer, particularly breast and colon cancer, in humans. To fulfill their signaling functions however, Src-family kinases must first be folded into an active conformation upon their synthesis in the cell then be maintained in this conformation. Although previous studies, including our own, have implicated a class of proteins called molecular chaperones in this process, little is known about how the folding of Src-family kinases by these proteins is achieved and regulated. The overall aim of this study is to determine how the folding of Hck, one member of the Src-family of tyrosine kinases, into a conformation that enables it to participate in signaling networks is achieved and regulated. It is expected that the results from this study will provide significant new insight into how this process might influence the ability of cells to respond to extracellular stimuli and potentially contribute to the conversion of a normal cell into one with tumourigenic properties. Findings from this project may be particularly important in the context of human cancer. A better knowledge of how the signaling activity of Src-family kinases is regulated by molecular chaperones might provide a new avenue of investigation for the identification of novel chemotherapeutic agents.Read moreRead less
The Structural Basis Of Ligand-Induced Activation Of The Insulin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$640,825.00
Summary
We aim to understand how insulin binds to and activates its cell-surface receptor. This information has implications for the design of anti-diabetic agents targetted directly to the insulin receptor. Diabetes is a global health problem and is classified by the World Health Organization as an epidemic. The results also have implications for the insulin-like growth factor receptor system and the design of anti-cancer therapeutics directed towards it .
Role Of FHA Domains As Protein-protein Interaction Modules In Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$191,973.00
Summary
The proper processing of information in cells involves the association of different proteins to signalling complexes. We will decipher the role the so-called FHA module plays in the formation of protein complexes. FHA modules are present in several proteins that are important for the repair of damaged DNA and the stability of chromosomes. Understanding the structure and function of this module will be relevant for various forms of cancer where DNA is damaged.
Investigating The Physiological And Biochemical Role Of SOCS5 In The Immune System
Funder
National Health and Medical Research Council
Funding Amount
$405,940.00
Summary
Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these proteins act to coordinate the body s immune defence against paras ....Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these proteins act to coordinate the body s immune defence against parasite infection. In other words, asthma is thought to arise through inappropriate IL-4 and IL-13 activity in the absence of a parasite infection. Extra IL-13 is commonly found in the lungs of asthmatics and is thought to help trigger asthma attacks. IL-13 is a validated target for drugs that could be used in the treatment of asthma. The SOCS genes were discovered in our laboratory and by genetically deleting the genes in mice we have demonstrated a critical role for SOCS1, SOCS2 and SOCS3 in regulating the immune response and the action of growth hormone. My hypothesis is that SOCS5 is an important physiologic regulator of the asthma response. This proposal will investigate the basic biochemical processes underlying the regulation of IL-4 and IL-13 action and the relationship to development of asthma and immune disease. I plan to induce asthma attacks in mice that lack the genes for SOCS4 and SOCS5. If the severity of the attacks is greater in the absence of these proteins this will indicate that SOCS4 and-or SOCS5 are important negative regulators of IL-4 and IL-13. This has the potential to open up a completely new strategy for the development of drugs that could be used in the prevention and treatment of asthma.Read moreRead less