Glial-neuronal-vascular Interactions In A Novel Transgenic Model Of Muller Cell Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$626,585.00
Summary
Muller cell disfunction is a feature shared by many retinal diseases. This project aims to study the contribution of Muller cell dysfunction to retinal neuronal damage and blood-retinal barrier breakdown in a novel transgenic model we recently generated. Results of this study will also be of interest to scientists and clinicians seeking to understand better and treat diseases of the central nervous system in general.
Epithelium-fibroblast Interactions In Response To Allergic Airway Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$235,526.00
Summary
The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immed ....The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immediately beneath them (fibroblasts) are important sources of mediators and structural matrix proteins that contribute to these processes. Under normal conditions, signals from these structural proteins are transmitted to the cells via specific adhesion molecules. However, in asthma epithelial cells are frequently damaged and detached, and fibroblasts appear to proliferate and undergo changes in their appearance. This projects aims to investigate the expression and function of specific cell adhesion molecules in the epithelium and fibroblasts following airway inflammation. Specifically, this proposal aims to determine which adhesion molecules are associated with upregulated proliferation and production of matrix proteins. We will also examine the effects of two novel mediators, thought to play a role in remodelling on the expression and function of these adhesion molecules. Proliferation of these cells and the altered deposition of matrix proteins may be a key feature of airway wall thickening and hyperreactivity that is a characteristic feature of asthma. The balance of deposition and breakdown of matrix proteins is regulated by a variety of mediators. Defining what regulates the expression and activity of adhesion molecules is of fundamental importance in determining how the normal repair processes may evolve into airway wall remodelling.Read moreRead less
Investigate Novel Functional Roles For PI 3-kinases In Platelets.
Funder
National Health and Medical Research Council
Funding Amount
$537,215.00
Summary
Platelets are small blood cells which have a well defined role in blood clotting. There is a growing body of evidence that platelets play an important role in a broad range of inflammatory diseases, and we have identified a key role for the platelet PI3K enzyme in controlling the pro-inflammatory function of platelets. This grant will examine the importance of PI3K in health and disease, and examine the potential therapeutic benefits of inhibiting platelet PI3K.
Negative Regulators Of Nuclear Import; Potential Links To Cancer
Funder
National Health and Medical Research Council
Funding Amount
$495,829.00
Summary
Trafficking of proteins into the nucleus is critical to mammalian cell function, relating strongly to developmental processes and cancer. We have identified a new class of molecule - negative regulators of nuclear import - that function to prevent entry into the nucleus of key regulators of the cell cycle-apoptosis, and have a potential link thereby to cancer. We propose to determine their mechanism of action, modulation by cellular signals, and how important this is to cell function-cancer.
Airway Smooth Muscle - Mast Cell Cross Talk In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
In Australia 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our community and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation because, without them, chronic inflammation leads to thickened airways with increased amounts of smooth muscle that contracts too much and too easily. However, corticosteroids may have side effects , particularly in children. In order to design safer more specific treatments for ....In Australia 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our community and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation because, without them, chronic inflammation leads to thickened airways with increased amounts of smooth muscle that contracts too much and too easily. However, corticosteroids may have side effects , particularly in children. In order to design safer more specific treatments for asthma, we need to know more about the pattern of inflammation that is specific for asthma and what chemical signals cause it. Then we will be able to target it more specifically. Recent research has demonstrated that in asthma, but not in bronchitis or in healthy people, inflammatory cells called mast cells are found in increased numbers down in the smooth muscle layer of the airways. Mast cells are key cells in all allergic reactions. In the airways they release mediators that contract the airways, induce mucous secretion and promote further inflammation. We think the effects airway smooth muscle cells and mast cells have on each other are central factors in causing the physical changes to the airways of asthmatics. We will identify what chemical messages released by the smooth muscle attract mast cells to it and once they are there, what the mast cells stick to on the smooth muscle. Then we will investigate how the two cell types interact with each other and affect each other. We will focus on how the functions of the smooth muscle cells are affected, especially those that would promote further inflammation and lead to increased amounts of more sensitive, more contractile smooth muscle. We will try to prevent each of the steps we identify with drugs that have very specific actions. This additional information may lead to the design of novel treatments for asthma that have fewer side effects.Read moreRead less