Therapeutic Potential Of The IL-3-IL-5-GM-CSF Common Beta Receptor To Treat Upper And Lower Allergic Airway
Funder
National Health and Medical Research Council
Funding Amount
$150,442.00
Summary
This research aims to develop new treatments for allergic diseases such as asthma and allergic rhinitis, which remain significant public health problems in Australia. We will develop new therapies with the potential to completely suppress acute and chronic allergic disease targeting a common receptor protein that controls multiple facets of allergic inflammation. We will test antibodies intended to treat human asthma using a novel mouse strain expressing the human form of this receptor.
This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on hu ....This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will characterise the chemical nature of this receptor and verify that it is functionally important in mast cell activation. Because mast cells reside in almost all body tissues and are also important mediators of host responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the blood of normal individuals and that the genes that encode these proteins are regulated by mediators that regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of allergy and may lead to the design of novel strategies to regulate the process. Results may have broader ramifications applicable to other inflammatory and infectious diseases.Read moreRead less
I am a research scientist measuring inhaled and exhaled bioaerosols, such as viruses and allergens, to determine their clinical role in human respiratory diseases, particularly asthma.
Mechanisms And Treatment Of Early Life Chlamydial Infection And Associated Asthma
Funder
National Health and Medical Research Council
Funding Amount
$616,195.00
Summary
Asthma is a serious respiratory disease that results from certain immune responses to allergens and there are no cures. Immune responses and lung structure may be permanently altered by respiratory chlamydial infection early in life that leads to reduced lung function and asthma but how this occurs is unknown. In this project we will determine how early life infections affect immune responses, lung function and asthma and test novel treatments and preventions for infection-associated asthma.
Fine Mapping Of Genes Underlying Asthma And Eosinophilia
Funder
National Health and Medical Research Council
Funding Amount
$278,000.00
Summary
Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent t ....Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent twins, we showed these measures to be genetically linked to two different regions in the genome. Closer examination of these regions found several genes that might be responsible for the linkage. In the present study, we plan to test which of these candidate genes actually causes elevated IgE level or eosinophil count. The approach is to compare the frequency of a putative gene in a child expressing that phenotype to that in their parents. Each child receives one copy of a gene from the father, and one from the mother, making up a complete genotype (two possibly different versions or alleles of the gene). Since each parent transmitted only one allele to the child, the remaining allele from each parent can be used to create a normal control genotype, that is guaranteed to come from the same ethnic background as the asthmatic child. Therefore, we will collect replacement blood samples in those familes where all the previously DNA has been used up in our earlier study. We will extract DNA, and measure the genotypes of parents and children at the 6 genes in our two regions that we think most likely to be involved in eosinophil count or IgE level. This family based test will allow us to decide which genes are genuinely associated with asthma in our population. We will also test if these genes interact with other genes thought to be asthma risk factors. Identification of novel genes involved in asthma will help understand and ultimately treat this condition.Read moreRead less
Role Of Zinc In The Respiratory Epithelium And Asthma
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example ....This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example, asthma affects 12% of adults and amongst these, 15% waken weekly or more often with their asthma while 6% are hospitalized annually. There is a need to understand the basic mechanisms underlying these diseases so that new strategies can be developed to modify bronchocondtriction and inflammation. The project will provide new knowledge concerning the physiology of Zn in the respiratory epithelium and interactions between Zn deficiency and oxidants on injury in the respiratory tract. The usefulness of easily accessible nasal epithelial cells as a measure of Zn and Zn transporter levels deeper in the respiratory tract will be assessed. The project encompasses a number of fields and utilizes in vitro cellular and animal models, as well as tissues from human subjects.Read moreRead less
Many approaches to the prevention and treatment of allergy and associated asthma are dependent on the identification of the allergens producing the inflammation. This applies to new methods of determining the exposure to allergens and measuring the effectiveness of procedures which minimise allergen exposure. Diagnostic and immunotherapeutic measures require reliable preparations of allergens. The presence of important allergens in extracts however can be variable and often low so it important t ....Many approaches to the prevention and treatment of allergy and associated asthma are dependent on the identification of the allergens producing the inflammation. This applies to new methods of determining the exposure to allergens and measuring the effectiveness of procedures which minimise allergen exposure. Diagnostic and immunotherapeutic measures require reliable preparations of allergens. The presence of important allergens in extracts however can be variable and often low so it important that the allergens be identified and monitored. It is also important that new forms of immunotherapy being developed consider the responses to all allergens. Allergy to the cat is, behind house dust mite, the second most frequent allergy associated with asthma in most developed countries and brief exposure to a cat frequently induces life-threatening attacks. Almost all of the study of cat allergens have concentrated on a single allergen called Fel d 1. Although it importance is undisputed critical reading of the literature show it is only responsible for 50% of the IgE binding in cat extracts and recent work on cross allergy to cat and dogs and experimental therapy based on Fel d 1 point to the importance of other allergens. Experience with other source of allergens has shown that at least several allergens are usually important. It is also apparent from other studies that some allergens which are difficult to detect in extracts, and cannot be readily studied by immunochemistry are important. This project will use both cDNA cloning and immunochemistry to identify and characterize the other cat allergens and determine there relative importance. In particular it intended that they can be used, along with Fel d 1, to develop new types of immunotherapy.Read moreRead less