Structural And Functional Properties Of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$188,623.00
Summary
Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protei ....Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protein tyrosine phosphatases, SHP-1 and SHP-2. We would therefore consider PECAM-1 as a new member of an emerging Ig-ITIM superfamily. Members of the Ig-ITIM gene family have both inhibitory-non-inhibitory receptors which upon ligation of specific receptors can globally stimulate or inhibit cellular activation in the context of B cells, Tcells, mast cells , endothelial cells or platelets. Balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease, to provoke immunological memory from vaccination and to dampen the extent and duration of platelet activation. Our investigations are focussing on the isolation and functional characterisation of PECAM-1 family members to define their role in regulating cell signaling pathways in vascular and haematopoietic cells. We predict that PECAM-1 has numerous undefined family members that exist as multiple isoforms as a product of separate genes, alternative splicing of discrete exons and single point mutations giving rise to conservative and non-conversative amino acid changes. The longer term potential of this study is to provide knowledge for understanding the structural and functional roles of PECAM-1 isoforms in physiological cells in health and disease. This knowledge could then be applied to provide targets for novel therapeutic interventions in the clinical management of autoimmune disease, humoral and inflammatory responses.Read moreRead less
Characterisation Of The Adiponectin Receptors - AdipoR1 And AdipoR2
Funder
National Health and Medical Research Council
Funding Amount
$445,158.00
Summary
The increasing incidence of cardiometabolic disease highlights an unmet need for novel therapeutic approaches. Greater understanding of the detail governing cardiometabolic function is required to provide a foundation to construct effective strategies. We will characterise 2 novel receptors that are important in the regulation and maintenance of cardiometabolic systems, seeking to identify strategies to enhance receptor, improve cardiometabolic function and reduce disease burden.
Molecular Pharmacology Of Chemokine Receptor Signalling In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$371,770.00
Summary
Molecular pharmacology is the study of how hormones, neurotransmitters and pharmaceuticals interact with our cells through receptors, which transfer a signal across the cell membrane to change the function of that cell. Chemokine receptors are recognised to play a role in the development of many cancers. Understanding how these receptors work has enormous implications for improving our ability to develop better anti-cancer treatments with fewer side effects.
Allosteric Targeting Of The Dopamine D2 Receptor: A Novel Approach For The Treatment Of Parkinson’s Disease And Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$469,644.00
Summary
The dopamine D2 receptor is a brain protein that is the target for drugs that are used in the treatment of schizophrenia and Parkinson's disease (PD). In both cases the current drugs have significant side effects because they simply act to switch the receptor off or on respectively. We will focus on a new class of drugs that, because they act to tune up or tune down the activity of the D2 receptor, may be a safer more effective approach to treat these disorders.
The Novel CXCR4/CCR7 Heterodimeric Chemokine Receptor Is A Key Determinant Of Breast Cancer Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$461,252.00
Summary
Novel cellular receptor has been identified that works as a switch to turn on cellular functions that are responsible for the metastatic dissemination of cancer cell to distant organs. The make-up and regulatory mechanisms of this novel receptor will be studied together with its potential utility as the marker of metastatic breast cancer.
This research will push the boundaries of current knowledge in receptor pharmacology and translate this knowledge into clinical outcomes. Receptors are proteins on the surface of our cells that bind hormones, neurotransmitters and pharmaceuticals. By better understanding the complexities of how these receptors work at the molecular level, the objective is to develop improved treatments and better clinical management for a range of medical conditions.
The Structure And Composition Of The T-cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$434,644.00
Summary
Our research will provide a fundamental advance in our understanding of how foreign viruses and pathogens trigger the immune system. Gaining a greater understanding of these central events will facilitate the design of novel therapies to treat immune associated disorders such as transplant rejection, autoimmune disease and some cancers.
New Mediators Of GPCR-growth Factor Receptor Transactivation
Funder
National Health and Medical Research Council
Funding Amount
$607,842.00
Summary
Hormones bind to receptors on the surface of cells. Receptors can modify each other’s function and this “cross-talk” is important for the receptors for a peptide hormone (termed angiotensin) and a growth factor receptor (EGFR), which are major regulators of the cardiovascular system. We have identified a number of mediators of the angiotensin-EGFR crosstalk and this current grant aims to use molecular and cellular and in vivo approaches to examine the molecular basis of their actions.
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how each of these components, the stimulating agent, the receptor and G protein, works in order to understand how the cells respond to various chemical signals. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. Understanding what actually is the role of these new players, and how they team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less