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
Dynamics And Mechanisms Of Immune Complex-mediated Skin Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$526,467.00
Summary
Type III hypersensitivity underlies a number of common autoimmune diseases, including rheumatoid arthritis and lupus erythematosus. These diseases are caused by the deposition of immune complexes (IC) and the accumulation of neutrophils within small blood vessels. We will use real time imaging to dissect in space and time the recruitment of neutrophils and IC deposition during type III hypersensitivity reactions in order to better understand the pathogenesis of these conditions.
Targeting Pathogenic TAR DNA-binding Protein 43 To Treat Frontotemporal Dementia And Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$687,444.00
Summary
Frontotemporal dementia and motor neuron Disease are rapidly progressive and fatal neurodegenerative diseases that affect people in their prime. Poor understanding of the processes that lead to these diseases have slowed drug development. Through innovative experimental design, we aim to decipher a novel disease mechanism that involves specific molecular interactions and translate these findings into new therapies for the diseases.
Host Metabolism And Responses Contributing To Flavivirus Replication And Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$592,772.00
Summary
We aim to determine how viruses affect the cells they infect, In particular how they can alter the metabolism and balance of lipids in cells and how this impacts the bodies capability to respond immunologically. We believe that by understanding these basic principles we can target ares fr antiviral therapeutic potential.
Characterising The Function Of Niche-derived Neuregulin 1 In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$994,246.00
Summary
Colorectal cancer affects thousands of Australians each year. A specialised cell population, named cancer stem cells, continuously produces new tumour cells. Defining mechanisms controlling the behaviour of these unique cells is critical to develop new drugs. We have identified that Neuregulin-1 is a key factor that enhances the action of cancer stem cells. We aim to study how colorectal cancer is mediated and whether targeting Neuregulin-1 is a promising therapeutic option.
Cancer Immunotherapy Utilizing A Novel Receptor For Programmed Cell Death-1 Ligand 2
Funder
National Health and Medical Research Council
Funding Amount
$577,857.00
Summary
Immuno-modulators utilize the patient’s own immune system to eliminate or slow the growth of cancerous cells. We have identified a novel immuno-modulator which could be a significant player in immune-modulation therapy for the treatment of cancer. We will use the development grant to develop a product which has significant potential to be the next generation treatment for cancer.
Specialised immune cells, called cytotoxic T cells, circulate through the body, and kill infected cells to protect us from disease. We discovered that a protein, DOCK8, is important for the regulation of T cell function. Importantly, humans with mutations in the DOCK8 gene suffer from a debilitating, and potentially lethal, immunodeficiency disease. This project will therefore elucidate the role of DOCK8 in immune cells, to better understand the consequences of DOCK8 deficiency for immunity.