Physical Determinants Of Lung Development Before And After Birth
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Survival at birth is critically dependent upon the ability of the lungs to take on the role of exchanging gases; a role previously performed by the placenta. The lungs must, therefore, have grown and matured sufficiently during fetal life, before they are required at the time of birth. Inadequate development of the lungs during fetal life is the most common cause of death and disease in newborn babies. This may be due to premature birth, when the lungs have had insufficient time to develop, or i ....Survival at birth is critically dependent upon the ability of the lungs to take on the role of exchanging gases; a role previously performed by the placenta. The lungs must, therefore, have grown and matured sufficiently during fetal life, before they are required at the time of birth. Inadequate development of the lungs during fetal life is the most common cause of death and disease in newborn babies. This may be due to premature birth, when the lungs have had insufficient time to develop, or it may be due to inappropriate lung development during fetal life. It is important therefore, to understand the mechanisms that control growth and development of the lung both before and after birth. During fetal life the lungs are filled with liquid which expands the lungs and provides a stretch stimulus causing them to grow. Previously we have shown that a reduction in the degree of fetal lung expansion causes lung growth to cease. Likewise, if we increase the degree of lung expansion in the fetus, we induce a rapid increase in fetal lung growth and maturation. This stimulus is so potent that it can reverse an existing lung growth deficit, thus enabling survival of the newborn. In this application we will investigate the mechanisms by which alterations in lung expansion induce growth and maturation of the lung. Specifically we will investigate the role of calmodulin in fetal lung growth, because the genes that encode it are activated when the lung cells are growing most rapidly. In addition, we will identify other genes that are turned on or off during rapid growth of the lung because those genes are likely to play important roles in the regulation of fetal lung growth and development. We will also investigate the underlying differences in the control of lung growth at different stages of gestation, as well as investigate factors that regulate lung growth after birth, particularly in prematurely born animals.Read moreRead less
Alveolar Epithelial Cell Differentiation And Apoptosis: Effects Of Preterm Birth, Corticosteroids And Stretch.
Funder
National Health and Medical Research Council
Funding Amount
$484,500.00
Summary
In the lung, gas exchange takes place in small terminal airsacs called alveoli. The internal surface of the alveoli are lined with 2 types of specialist cells, the type-I and type-II cells. Both cells are essential for the normal functioning of the lung; type-I cells provide a thin barrier for the gas exchange, whereas type-II cells produce the surface-active material, surfactant. In order to survive after birth, the lungs of the newborn must have appropriate numbers of each of these cell types. ....In the lung, gas exchange takes place in small terminal airsacs called alveoli. The internal surface of the alveoli are lined with 2 types of specialist cells, the type-I and type-II cells. Both cells are essential for the normal functioning of the lung; type-I cells provide a thin barrier for the gas exchange, whereas type-II cells produce the surface-active material, surfactant. In order to survive after birth, the lungs of the newborn must have appropriate numbers of each of these cell types. However, babies that are born very prematurely have few, if any, mature cells as most are non-specialised cells that possess none of the characteristics of mature type-I and type-II cells. Therefore, the lungs of very preterm babies have low levels of surfactant, are prone to injury and infection and are not efficient in the exchange of oxygen and carbon dioxide. As such, these infants are at high risk of developing chronic lung disease which is a serious debilitating disease that has long term health implications. We believe that the non-specialised cells are more prone to injury and cell death than mature cells which makes the very premature infant more susceptible to the development of chronic lung disease. As the survival and respiratory health of these infants depends upon most type-I and type-II cells maturing after birth, it is critical to understand the factors that regulate their maturation. This information will allow the development of treatments that can enhance the maturation of these cell types. This application is focused towards understanding the factors that control maturation of type-I and type-II cells, as well as the role of the non-specialised cells in the development of chronic lung disease in babies that are born very prematurely.Read moreRead less
Biomarkers And EGFR Inhibitor Treatment Of Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer p ....Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer pathways in the cell, has highlighted the need for detailed knowledge about how these therapies work at the molecular level, so that we can make best use of them. The laboratory studies will be on tissues taken from patients with NSCLC who are receiving chemotherapy then going on to surgery to have the cancers removed. Tumour samples will be taken prior to treatment, and then the surgical resection will also be analysed. Sequential blood samples will also be taken. Prior to surgery, patients will receive a 9 week course of chemotherapy with cisplatin and docetaxel to shrink the cancer. In addition, some patients will be randomised to receive cetuximab along with chemotherapy. In the laboratory, we will investigate whether various measures of activation of the EGFR pathway in the cancer and in blood predict for response to cetuximab. We will also investigate how the changes in tumour with cetuximab treatment differ from tumours not treated with the drug. We will be examining the genes and proteins of EGFR and those of a number of related pathways. a number of related receptor, along with From this we will attempt to understand which patients benefit most from the drug and also in what specific ways the cancer cells are affected by the treatment.Read moreRead less
Glucocorticoid Resistance: Identifying New Anti-inflammatory Drug Targets
Funder
National Health and Medical Research Council
Funding Amount
$453,287.00
Summary
The control of chronic inflammatory diseases such as asthma involve use of drugs related to the steroid hormone cortisol. Up to 40% of patients with more severe disease respond poorly or not at all to these drugs. The remaining non-steroid treatments are only partially effective. Poor disease control is a great health and economic burden. We have identified a molecular mechanism for steroid resistance and propose new studies to identify novel drugs that act to reverse steroid resistance.
In the past few years, an expanding number of small RNAs (ribonucleic acids) have been discovered that play a critical part in regulating multiple steps involved in the development of human tumors. One of the genes critically implicated in the development several human cancers (including breast, lung, brain, prostate and colon) is the epidermal growth factor receptor (EGFR). As a consequence, the EGFR is a key target for new biological therapies designed to reduce signaling through the EGFR path ....In the past few years, an expanding number of small RNAs (ribonucleic acids) have been discovered that play a critical part in regulating multiple steps involved in the development of human tumors. One of the genes critically implicated in the development several human cancers (including breast, lung, brain, prostate and colon) is the epidermal growth factor receptor (EGFR). As a consequence, the EGFR is a key target for new biological therapies designed to reduce signaling through the EGFR pathway resulting in reduced growth. Using a computer-based algorithm, we have recently discovered that one of these small RNAs (or microRNAs) is a master regulator of EGFR levels in human breast and lung cancer. When we add the specific microRNA to cancer cells with excess EGFRs and low levels of microRNA, we can abolish EGFR expression almost completely, associated with cell death. From our studies, it appears that the level of this microRNA in tissues relates inversely to the level of EGFR. As the major site of expression of this microRNA is in the brain, we were intrigued to demonstrate that the normally high level of the microRNA is lost in brain cancers (or gliomas) which are associated with high levels of EGFR. Thus, the loss of microRNA may enable the tumor to develop, suggesting that the microRNA may act as a tumor-suppressor . In this project, we will investigate the functional role of this microRNA in a range of human tumors, determine if it can work synergistically with other new biological therapies targeting the EGFR signaling pathway, identify some of its binding partners and determine the levels of EGFR and the microRNA prospectively in a cohort of gliomas. These studies will determine the functional role of the microRNA and form the foundation for further studies to consider strategies to deliver the microRNA for therapeutics.Read moreRead less