Department of Medicine – Alfred Hospital
TRANSPLANTATION IMMUNOLOGY / RENAL DISEASE GROUP
Mechanisms of chronic injury in cardiac allografts
Supervisor: Dr Alicia Stein-Oakley (Tel: 9903-0539)
Email: Alicia.Stein-Oakley@med.monash.edu.au
Location: Dept of Medicine, Monash Medical School, Alfred Hospital
Description:
Cardiac transplantation is currently the therapy of choice for end-stage heart disease resistant to other medical or surgical therapy. The main cause of graft and patient loss after the first post transplant year is cardiac allograft vasculopathy. This project is part of an extensive prospective longitudinal study of endomyocardial biopsies from patients with cardiac allografts. The aim of the study is to analyse specific features of biopsies during the first year post transplantation, to determine their value as predictive factors for the subsequent development of cardiac allograft vasculopathy. The factors to be examined include fibroblast growth factor-2, fibroblast growth factor -9, plasminogen activator inhibitor-1, vascular endothelial growth factor and genes of the renin-angiotensin and endothelin systems.
Techniques: Immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, in situ hybridisation
Apoptosis in tolerance induction
Supervisors: Dr Alicia Stein-Oakley (Tel: 9903-0539), Prof Napier Thomson
Email: Alicia.Stein-Oakley@med.monash.edu.au
Location: Dept of Medicine, Monash Medical School, Alfred Hospital
Description:
Peripheral transplantation tolerance can be induced by donor specific blood transfusions given under cover of cyclosporine A. Increased apoptosis has been implicated in the induction of tolerance through other mechanisms, such as increased antigen load. Spleen and thymus have been collected from AS rats, at different time points during the induction of tolerance to DA recipients, by donor specific blood transfusion. This project will assess changes in apoptotic cell numbers and in the regulation of apoptotic pathways in these tissues.
Techniques: Immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, gel electrophoresis, in situ hybridisation, TUNEL technique
Cytokine gene polymorphisms in progression of diabetic renal disease
Supervisors: Dr Alicia Stein-Oakley (Tel: 9903-0539), Prof Napier Thomson
Email: Alicia.Stein-Oakley@med.monash.edu.au
Location: Dept of Medicine, Monash Medical School, Alfred Hospital
Description:
Diabetic nephropathy is the second most common cause of renal failure in Australia. A genetic basis for diabetic nephropathy is supported by both ethnic and family studies. Various cytokines have been shown to play important roles in the development of renal injury. Genetic polymorphisms have been described in genes of such cytokines. In particular, the G to A transitions at -308, and at -238 in the tumor necrosis factor a promoter, the LeuÆPro and the ArgÆPro transitions at codons 10 and 25 respectively in the transforming growth factor b1 gene, and the G/A polymorphism at position -1082 in the interleukin-10 gene are associated with levels of cytokine production and /or export.
There are various models representing different theories on the pathogenesis of diabetic nephropathy. Poor glycemic control is necessary but not sufficient for its development, and it interacts with genetic susceptibility. This project will use a case-control study design, which can detect major, moderate and minor gene effects, to test the hypothesis that specific cytokine genetic polymorphisms significantly mediate progression of renal disease in Type 2 diabetes patients.
Techniques: DNA extractions, amplification refractory mutation system (ARMS)- polymerase chain reaction, gel electrophoresis, allele detection using the ABI Prism 7900 HT, use of Access database, statistical analyses.
RESPIRATORY MEDICINE GROUP
Much of Respiratory Medicine's research effort over the last six years has involved the collection and archiving of lung samples from asthmatic subjects and lung transplant recipients. The broad strategy that underpins the following projects is to make use of human samples that have already been collected. This represents a tremendous opportunity for students to take part in research that will potentially increase understanding of the pathogenesis of asthma and chronic rejection of lung allografts.
These projects will utilise methodological approaches that have been proven in house, but which also represent work which is at the forefront of peer reviewed research. It is envisaged that these projects may lead to higher degree projects and in the past departmental scholarships have been made available in order to facilitate this.
LUNG TRANSPLANT PROJECT
Airway changes in chronic lung transplant rejection
Supervisor: A/Professor Trevor Williams
E-mail: trevor.williams@med.monash.edu.au
Location: Dept.Medicine, Monash Medical School, Alfred Hospital
Over 50% of lung transplant recipients will develop evidence of narrowing of small airways within 3 years following the transplant operation. We have developed an international reputation for defining the process at its end stage and are presently studying whether a change in immunosuppression will lead to an alteration in the development of this "so-called" airway remodelling.
Immunostaining for inflammatory enzymes in airway biopsies in lung transplant recipients
Supervisor: A/Professor Trevor Williams
E-mail: trevor.williams@med.monash.edu.au
Location: Dept.Medicine, Monash Medical School, Alfred Hospital
Our Respiratory Immunology Group has collected a large number of biopsies from patients following lung transplantation. We have developed techniques for assessing a number of potentially relevant enzymes (e.g. Nitric oxide syntheses and steroid dehydrogenises) in these tissues. Our broad hypothesis is that the immune response to the lung allograft results in the production of cytokines that promote laying down of collagen (profibrogenic cytokines). Defining the cytokine profile may allow us to detect early the development of chronic rejection and assess the modifying effects of different immunosuppression strategies.
DERMATOLOGY GROUP
Female androgenetic alopecia
Supervisor: Dr R Sinclair
Email: sinclair@svhm.org.au
Location: Dermatology Unit, Alfred Hospital
Hair loss is a common and often distressing problem affecting adult women. There are a
number of possible causes of hair loss including childbirth, systemic illness, drug reactions, as well as androgenetic alopecia. In addition some cases are idiopathic.
This project aims to study in detail the morbidity and natural history of hair loss in women. Having previously identified 330 female patients with diffuse hair loss, of whom 220 have histologically proven androgenetic alopecia, the focus of this research is to apply previously evaluated quality of life questionnaires to these women to assess morbidity, and the influence of treatment on their quality of life. In addition, as the natural history of androgenetic alopecia in females has not previously been studied, untreated patients will be recruited via media advertising, and the natural history of their hair loss monitored by standardized clinical photography and phototrichogram hair count data.
BONE MARROW TRANSPLANTATION / CLINICAL HAEMATOLOGY
Evaluation of apoptotic mechanisms in multiple myeloma cell lines and patient derived primary tumours
Supervisor: Dr A Spencer
Email: aspencer@netspace.net.au
Location: Bone Marrow Transplant Unit, Alfred Hospital
We have previously evaluated the efficacy of a novel potential anti-tumour agent TRAIL / Apo-2 (TNF-alpha receptor apoptosis inducing ligand) in primary tumours derived from patients with multiple myeloma. Our data suggests that approximately 30% of tumours are sensitive to TRAIL but that nearly all (>95%) express cell surface effector receptors for TRAIL. This suggests that functionally relevant abnormalities of the TRAIL receptors are present or alternatively that intra-cellular anti-apoptotic mechanisms prevent TRAIL induced tumour cell apoptosis. This study will investigate TRAIL apoptotic pathway related components in cell lines and primary tumours focusing on differences between TRAIL sensitive and insensitive cells and variations induced by exposure to effective concentrations of TRAIL. If a common mechanism for TRAIL resistance can be demonstrated combination therapeutic strategies including TRAIL could be explored.
Mutations in components of the TRAIL apoptosis pathway in multiple myeloma
Supervisor: Dr A Spencer
Email: aspencer@netspace.net.au
Location: Bone Marrow Transplant Unit, Alfred Hospital
Multiple myeloma is a malignant expansion of plasma cells characterised by multiple genetic abnormalities and a high degree of resistance to conventional chemotherapeutic strategies. We have demonstrated that 30% of primary tumours show sensitivity to the potential novel anti-tumour agent TRAIL (TNF-alpha receptor apoptosis inducing ligand) despite apparent expression of cell surface effector receptors in most cases. Mutations of an alternative apoptosis inducing cell surface receptor FAS / Apo-1 have previously been demonstrated in multiple myeloma. This study will analyse the key components of the TRAIL apoptotic pathway in a search for functionally relevant mutations that may explain the TRAIL resistance seen in the majority of primary tumours.
CLINICAL PHARMACOLOGY / THERAPEUTICS GROUP
Autonomic Effects of Lung Transplantation
Supervisor: A/Professor H Krum, Dr M Naughton, Associate Professor T Williams
Contact: Associate Professor H Krum (Tel: 9903 0042 / 0417 325 834)
Email: henry.krum@med.monash.edu.au
Location: Clinical Pharmacology / Respiratory Medicine, Alfred Hospital
Background - Patients who have undergone lung transplantation may have disordered autonomic function, however this has been poorly characterised to date.
Lung transplantation involves decentralisation of vagal afferent input whilst vagal input to the heart is preserved. Therefore lung transplantation provides an excellent model in which to assess the effect of vagal afferent denervation in man.
Methods - We will study the autonomic effects of lung transplantation in 20 lung transplant recipients and compare this to 20 age-and sex-matched control subjects. Parameters to be assessed include heart rate variability as a measure of autonomic function, non-invasive measures of baroreflex sensitivity, cold pressure testing and effects of tilt. The effect of controlled breathing to simulate Cheynes-Stokes respiration on autonomic function will also be assessed in these groups.
Implications - The information obtained from these studies will be of benefit in ascertaining the effect of afferent vagal denervation in man and by assessing autonomic derangements in lung transplant patients, may be of benefit in predicting potential for future cardiac events.
CLINICAL NEUROSCIENCES GROUP
Clinical correlates of recently developed otolith function tests
Supervisor: Dr. John Waterston (Tel: 9276 2552)
Email: john.waterston@med.monash.edu.au
Location: Oto-Neurology, Alfred Hospital
Traditional vestibular function tests assess only the functional integrity of the semicircular canals. Until recently, no practicable routine tests of otolith organ function existed.
However, the Alfred Neuro-otology laboratory has now added two new tests of otolith function to its capabilities: static bias testing (judgement of the horizontal in the absence of visual environmental clues) and vestibular-evoked myogenic potentials (recorded in sternocleidomastoid after high intensity auditory stimuli, which cause saccular activation). This project would address the correlation of abnormalities on these new tests with clinical syndromes and with traditional tests of vestibular (semicircular canal) function.
Expression of proteins involved in Spinocerebellar Ataxia and investigation of protease distribution in the brain.
Supervisors: Prof. E Storey and Dr L Kelly
Phone: 9276 2552
Email: Elsdon.Storey@med.monash.edu.au
Description: Huntington's Disease (HD) and 8 other neurodegenerative disorders are caused by the expansion of a polyglutamine tract. Each of the proteins associated with these disorders is ubiquitously expressed however only specific regions of the brain are affected. Our hypothesis is that the protein is only toxic once cleaved by specific proteases. It is the distribution of these enzymes that determines which part of the brain is affected. This project aims to express the SCA3 and SCA7 protein in E. coli with and without the polyglutamine expansion. Once expressed the protein will be used as substrate to assess regional specific proteolysis.
Techniques: Cloning and expression, Western blotting, densitometry analysis.
Validation and clinical correlation of upper limb ballistic tracking movement recordings and tapping regularity in cerebellar disease.
Supervisor: Professor Elsdon Storey, Ms Kate Tuck (Tel: 9276 2552)
Email: elsdon.storey@med.monash.edu.au
Location: Neurosciences, Alfred Hospital
Quantitation of cerebellar dysfunction is difficult, although a number of subjective rating scales such as the International Cooperative Ataxia Rating Scale have been published. Movements which are "aimed and fired" - performed too rapidly for correction to occur during the movement - are termed "ballistic". Overshoot on ballistic tracking movements is a useful clinical test of cerebellar dysfunction, and should particularly reflect dysfunction of the lateral zone of the neocerebellum. In conjunction with a biomedical engineering student, we have developed a laboratory version of the ballistic tracking test, measuring peak velocity / peak acceleration / duration of acceleration /overshoot versus target displacement. Dysdiadochokinesis refers to irregularity of repetitive movements, and is judged clinically. We have begun recording tapping rates using tremor recording equipment, and plan to analyse rate and variability in ataxic patients and controls. This project would investigate the reliability of these measures in cerebellar disease, and explore the correlation with clinical and MRI findings and with the genotype in various dominant spinocerebellar degenerations.
Novel proverbs test of frontal-executive function
Supervisor: Professor E Storey (Tel: 9276 2552)
Email: elsdon.storey@med.monash.edu.au
Location: Neurosciences, Alfred Hospital
One method whereby clinicians have traditionally tested abstraction is by asking patients to interpret proverbs. There are difficulties with this method, however, including differing exposure to the proverbs usually used due to differing sociocultural backgrounds, and the likelihood that interpretation of proverbs well-known to the patient may reflect semantic memory more closely than "abstraction". In an attempt to examine these points and increase test validity, a novel proverbs test has been developed together with an MCQ answer format, in which twelve novel proverbs are randomly intermixed with six known proverbs The purposes of this study are to refine the novel proverb battery by examining the contribution of each novel proverb to the overall score in elderly patients, to correlate the novel proverb score with other bedside measures of frontal-executive function and with estimated premorbid FSIQ, and to test the hypothesis that the score on novel proverbs will not correlate tightly with that on known proverbs, reflecting the contribution of semantic memory to the latter.
The role of APP and APLP2 in neurite outgrowth
Supervisors: Dr L Kelly, Professor E Storey (Tel: 9276 2552)
Email: elsdon.storey@med.monash.edu.au
Location: Neurosciences / Dept of Medicine, Alfred Hospital
APP, the amyloid precursor protein of Alzheimer’s disease, and its homologue APLP2 are found in a segmental distribution on the surface of neurites in cortical neurons in primary culture. Earlier work on the function of APP suggests a role in neurite-substratum adhesion.
We postulate that there will be functional redundancy between APP and APLP2 in this regard. This project aims to investigate the effect of removing APP, APLP2, or both on neurite outgrowth and branching using time-lapse videomicroscopy and computerised analysis of neurons cultured from gene knockout mice lacking APP, APLP2, or both. This is an entirely laboratory based project, which will also enable the acquisition of skills in tissue culture.
INFECTIOUS DISEASES GROUP
Supervisors: Prof S Wesselingh (Tel: 9276 3087)
Dr J Martin (Tel: 9903 0762)
Email: s.wesselingh@alfred.org.au jenny.martin@med.monash.edu.au
Location: Depts Medicine & Microbiology, Monash Medical School
Two or three vacancies.
Development of an oral plant-derived vaccine for measles
In the developing world over a million malnourished infants die annually from measles because of poor coverage of the existing measles vaccine making measles one of the main causes of infant mortality. To overcome these problems new measles vaccination strategies need to be developed. This project will investigate the development of an "edible" oral vaccine to the measles virus through the expression of measles antigens in plants. We plan to test the hypothesis that orally administered measles antigens derived from transgenic plants will evoke a protective immune response, and that oral immunogenicity can be enhanced by targeting measles H protein to the gastrointestinal mucosa, through genetic fusion of the protein to natural mucosal binding proteins.
Neuropathogenesis of HIV Dementia
Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV) infection. We have previously demonstrated a correlation between the severity of dementia, macrophage activation, and the production of neurotoxins. However, recently we have obtained data that suggest a significant role for astrocytes in the development of dementia.
We hypothesise that non-productive HIV infection of astrocytes leads to a loss of astrocyte function, increased astrocyte apoptosis and a consequence in the levels of neurotoxins.
Viral encephalitis
This project involves the use of Sindbis virus to investigate the immune response generated in the brain and the possibility of using an orally administered (transgenic plant) vaccine to prevent viral infections of the central nervous system.
Methicillin Resistant Staph aureus
The project involves the development of molecular typing methods which will then be used to aid the control of MRSA infections which continue to be a major problem in hospital settings.
|
