TGF-beta Receptor Type III In Normal And Malignant Liver Growth: Modulation Of TGF-beta Activity
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, ter ....The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, termed the type I, II and III TGF-beta receptors. The type I and II receptors are required for transmitting the TGF-beta signal to the nucleus of the cell. Existing data suggest that the type III receptor is not required in TGF-beta signaling but is required for the regulation of TGF-beta levels at the cell surface. However, the function of this receptor and its role in TGF-beta mediated regulation of cell growth and survival is poorly understood. Our earlier work indicated that the TGF-beta type III receptor is particularly important for limiting TGF-beta activity during normal liver development. The currently proposed research will examine the effects of type III receptor deficiency on liver cells in the adult mouse in order to determine whether alterations in cell growth and survival occur in the absence of this receptor. Becauses TGF-beta is a key regulator of liver growth and altered levels of TGF-beta in liver have been demonstrated to lead to liver cancer in mice, we anticipate that targeting the deletion of the type III gene to liver cells will provide a system in which to study compromised regulation of cell growth. This work is therefore expected to yield information relevant to the role of this receptor in TGF-beta regulated processes in normal and cancerous growth. Because the type III receptor appears to control the level of TGF-beta activity, this work will allow further evaluation of the potential for therapeutic uses for type III receptor-like agents.Read moreRead less
Affinity-based Profiling Of Bacterial Fe(III)-siderophore Receptors: Design Strategies For Antibiotics And Iron Overload
Funder
National Health and Medical Research Council
Funding Amount
$275,016.00
Summary
In order to establish an infection, bacteria compete with the host for iron, which is in scarce supply. To access iron, bacteria produce compounds called siderophores which bind iron strongly. The iron-siderophore complex, which is unique to each bacterium, is recognised by specific receptors at the bacterial cell-surface and imported for use. In this project, we are using modified siderophores as platforms for bacteria-specific drug design with the aim of producing new antibiotics.
Randomised Study Of Radiotherapy (RT) Or ChemoRT To Palliate Symptoms Of Advanced Oesophageal Cancer (OC)
Funder
National Health and Medical Research Council
Funding Amount
$236,375.00
Summary
Cancer of the oesophagus (gullet) causes swallowing problems (dysphagia) by narrowing the gullet and harming food movement to the stomach. >90% of patients with oesophageal cancer (OC) have dysphagia. OC is common, representing >1% of all cancer diagnoses, but is rarely curable, >80% of patients having disease beyond the oesophagus at presentation. Overall survival is thus poor with <10% of patients alive at 3 years. Most have disease obstructing the gullet and thus most patients suf ....Cancer of the oesophagus (gullet) causes swallowing problems (dysphagia) by narrowing the gullet and harming food movement to the stomach. >90% of patients with oesophageal cancer (OC) have dysphagia. OC is common, representing >1% of all cancer diagnoses, but is rarely curable, >80% of patients having disease beyond the oesophagus at presentation. Overall survival is thus poor with <10% of patients alive at 3 years. Most have disease obstructing the gullet and thus most patients suffer dysphagia as they come to terms with dying. This affects both the patient's ability to maintain nutrition and impinges on all areas of quality of life (QoL). Enjoying food is a pleasure of life and an inability to swallow food, water and saliva causes a significant loss of personal self esteem. Relief of dysphagia is the highest priority for treatment. This must be balanced against toxicity of treatment. It is surprising that patients and their doctors must consider this with very little scientific data to help their decisions. The trial uses a simple 2 arm randomisation, radiotherapy (RT) 35Gy in 15 fractions, versus the same with chemotherapy (Cisplatin and Fluorouracil). Both the RT schedule and chemotherapy are commonly used in Australia for this and other cancers. This is the first trial in the world to prospectively assess RT and the first to compare the effect of adding chemotherapy. The trial will:- 1. establish a new method of assessing dysphagia and QoL in all patients with OC using a set of specific questions(EORTC-QLQ-C30+oesophageal module). 2. quantify response and toxicity of a common RT schedule. 3. evaluate the extra benefit and toxicities of chemotherapy. 4. evaluate patient and tumour factors determining outlook, and response to treatment. 5. provide a bench mark for trials of new chemotherapy agents and different RT schedules. The trial will guide management and provide information for incurable patients even if both arms are similar in their effect.Read moreRead less