| NOTE: The CRC for Diagnostics formally ceased operations in September 2007. Some of the research programs formed the basis of a new CRC for Biomarker Translation.
The new CRC will develop antibody-based therapeutics and diagnostic tests that target cell surface molecules (biomarkers) expressed by white blood cells or cancer cells. These antibodies or “magic bullets" target the cells involved in major diseases, including autoimmune disease and cancers. The new therapies and tests are expected to transform the management of these diseases and make Australia a competitive force in the rapidly growing, multi-billion dollar antibody therapeutic market.
For further details, contact Professor Mark Hogarth Tel +61 03 9287 0685 or email pmhogarth@burnet.edu.au
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CDx Research Program to 2005
CDx developed and exploited diagnostic
platforms to enable diagnosis, monitoring and screening
for selected diseases, conditions and predispositions.
CDx realised these benefits through bringing together
the leading Australian-based diagnostic research organisations,
Australia’s major medical diagnostics users and
utilising effectively key international collaborators.
An innovative education program for under-graduate,
post-graduate and post-doctoral levels underpinned a commitment
to contributing to biotechnology and developing a thriving
Australian diagnostics industry.
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The research program discovers novel
diagnostic targets and develops both high affinity reagents
and high-sensitivity reporter systems. This is achieved
through 5 integrated and collaborative projects; Protein
Profiling (for novel Biomarker identification), Genome
Diagnostics (for SNP biomarkers), High-Affinity Reagents
(both protein and peptide libraries) and a core focus
on Infectious diseases and high-sensitivity Reporter
Systems.
The participants provide collaborative platform technologies;
eg the discovery of novel biomarkers through analysis
of molecular interactions, genomics and proteomics together
with selection of complementary high-affinity diagnostic
reagents.
CDx ouputs include the development of diagnostic platform
technologies, with particular emphasis on innovation
in “point-of-care” diagnosis, molecular
arrays and novel opportunities for flow cytometry and
high-sensitivity signal generation and capture for rapid
quantitative assays. |
Subprogram 1: Protein Profiling
Leaders: Dr Ian Nicholson, Professor Nick Hoogenraad, Professor Heddy Zola
Objectives
To identify protein expression profiles for the diagnosis and
monitoring of autoimmune diseases
Background
Many disorders involving the immune system are multifactorial
and cannot be diagnosed on the basis of a single marker. This
project involves the application of various technologies for
discovery of new lymphocyte cell surface molecules that will
be used to establish diagnostic protein expression patterns.
These patterns can be assayed using high affinity reagents
in a number of formats such as multiparameter flow cytometry,
bead-based flow assays for soluble molecules, and mass spectrometry-based
determination of protein expression.
CDx is well positioned to make significant advances
in biomarker discovery and engineering using multi-parameter
and high throughput screening technology. Expression profiling
of protein and mRNA using array technology will allow the
establishment of diagnostic panels for autoimmune diseases.
Subprogram 2: High Affinity Reagents
Leaders: Associate Professor Mick Foley, Dr Stewart Nuttall, Dr Kim Wark
Objectives
To identify novel high affinity reagents and generate
new platforms for library construction. Background IP
from the former CRC for Diagnostic Technologies initially
will be exploited to gain maximum benefit from existing phage
and ribosome libraries. The reagents will have exquisitely
high affinity against a range of commercially important target
molecules, some derived in collaboration with Project 1 (Protein
Profiling). This project will have two streams; one
focusing on the design, development and generation of new
libraries based on compact protein domains (CPDs) or random
peptides, and the second on the development of novel molecular
evolution processes. A key goal is to develop a process
for rapid screening of these peptide and protein libraries
on human antibodies to identify and construct mimics of infectious
pathogens for inclusion in diagnostic assays. In the longer
term, protein and peptide reagents diagnostic of diseases
whose aetiology is complex (or even unknown) will be developed
and affinity enhancement technology shall be established.
Background
Preparation of pathogenic organisms or recombinant proteins
for identifying antibodies in diagnostic assays is time consuming,
expensive and potentially hazardous. Replacement of
such diagnostic capture reagents with sets of simple peptides
or protein domains engineered with the desired specificity
would improve stability, lower production costs, and provide
scope for rapidly modifying such assays when new variants
arise. Current peptide and antibody libraries do not
contain high-affinity binders against many of the most important
diagnostic targets (e.g. active sites or clefts in enzymes,
cancer markers, viruses and micro-organisms). Further,
Project 1 (Protein Profiling) will produce a large range of
new molecular targets, each requiring an associated ‘diagnostic’
binding reagent. This project’s novel protein library
and selection approaches will complement existing peptide
and antibody libraries for production of high affinity reagents.
The approach includes technology for the manipulation of affinity
to create high affinity binders.
In many cases early diagnosis will have a significant
impact on treatment success and will improve prognosis.
Large libraries of random peptides and protein domains can
be searched by phage and ribosome display using sera from
individuals infected with the desired pathogen. Peptides
isolated by this approach will mimic features of the protein
that induced the antibodies and if presented appropriately
will capture these antibodies from infected sera, hence, ‘short
circuiting’ the traditional approaches of finding antigens
suitable for use in diagnosis of many diseases of unknown
aetiology. The identification of peptides that
bind specifically to antibodies present in sera from all patients
with such a disease, but not to normal sera would be a significant
development for the early identification of these disease
states. This project builds on, and extends CDx’s expertise
in molecular evolution processes.
For further information about the High Affinity Reagents
Sub-program, please download a copy of our brochure 
0.15 MB HAR.pdf
Subprogram 3: Genome Diagnostics
Leaders: Professor Ross Young, Dr Michael Fenech
Objectives
Three sub-projects share a common objective of identifying
human genome SNPs and other markers that would be useful for
the diagnosis of clearly defined human phenotypes whether
they be human physical traits, genome stability or prostate
cancer. The projects also are tied together as a profitable
cross-node collaboration by the use of a common approach for
identifying phenotypically important SNPs by use of population
wide whole genome SNP association studies using Affymetrix
SNP chips capable of interrogating 100,000 SNPs distributed
across the human genome. This approach will also incorporate
the use of core human population genetics expertise in genome
wide linkage disequilibrium analysis to identify SNPs that
contribute to the phenotype of interest.
Human Physical
Characteristics
The present market for genetic analysis is limited to a small
number of genetic diseases and some forensic and paternity
applications in a small number of highly specialised laboratories.
The forensic applications involve the comparison of non-coding
repeat sequences and require a suspect to have been identified.
It would be of immense benefit to be able to analyse crime
scene DNA samples to gain information about the appearance
of the perpetrator of the crime. The aim of this project is
to determine the DNA polymorphisms (SNPs) that result in the
range of physical appearances in the human population. We
will generate a profile of useful SNPs involved in physical
traits for development of forensic identification assays.
For example we are looking at characteristics such as pigmentation,
height/weight and facial morphology by comparison of DNA sequences
in population samples of differing phenotypes.
For further information
about the Human Physical Characteristics project, please download
our brochure
0.18 MB HUM.pdf
Prostate Cancer
SNPs
The overall aim of this project is to identify genes in the
human genome that are associated with increased susceptibility
to prostate cancer using a whole genome linkage disequilibrium
scan with Affymetrix SNP chips. We then plan to study the
candidate genes identified using this approach to characterise
the functional SNPs that cause the increased susceptibility
to prostate cancer so that they can be used as a predictive
diagnostic for prostate cancer. It is also likely that such
an approach might identify a protein product or metabolite
that will serve as a target for improved prostate cancer diagnosis.
Any candidate genes will also be useful starting points for
tailoring improved therapy for Prostate cancer.
Radiation Sensitivity
There are three major objectives of this sub-project.
- To develop a predictive test for
radiation sensitivity in prostate cancer patients undergoing
radiotherapy for the purpose of preventing tissue morbidity
in the colon and rectum (i.e. proctitis). This test will
be based the micronucleus index following an in vitro
radiation challenge test and single nucleotide polymorphisms
in candidate genes involved in DNA repair and antioxidant
response.
- To use whole genome SNP association
studies to search for SNPs involved in radiation sensitivity
phenotypes to discover novel genetic markers for radiation
sensitivity.
- To develop a predictive test
for prostate cancer risk based on the micronucleus index
of genome instability and SNPs identified in genes relevant
to genome instability in the studies described above (e.g.
folate metabolism and DNA repair genes).
Subprogram 4: Infectious Disease
Diagnostics
Leaders: P.Giffard & P.Timms
Objectives
To develop generic, cost effective, adaptable and robust methods
and reagents for infectious agent detection, quantification,
and strain typing. Effective strategies for the
rapid identification of polymorphisms optimal for microbial
profiling will be developed as well as novel market-driven
niche products for specific infectious disease detection.
Background
Diagnostic and public health microbiology present a range
of exciting opportunities for the application of novel technologies.
The large number of potential target organisms combined with
great variations in time and place of infectious disease ecology
mean that robustness and speed of diagnostic and typing methods
are essential. Furthermore, “traditional” microbiology
will be largely superseded by DNA-based methods because the
potential robustness, flexibility and sensitivity of these
methods, makes them ideally suited to the detection and profiling
of microorganisms. The rapid expansion of publicly-available
comparative sequence data for infectious disease agents will
drive a methodological revolution and expertise in CDx in
the monitoring. The mining of such databases for highly
informative polymorphisms is an essential complement to the
technology IP. Consequently, CDx will foster the development
of bioinformatics/ bacterial population biology skills in
this area and protect any IP generated. Experience and
IP in robust solid phase amplification based DNA diagnostic
methods, together with expertise in the bioinformatics of
infectious agents will provide a potent resource for the rapid
development of specific applications in infectious disease
diagnostics. Through close collaboration with commercial and
supporting partners, a number of potential targets have been
identified and these will be our initial foci for test development.
For further information
about Chlamydia Detection, please download a copy of our brochure
0.16 MB CHLAMYDIA.pdf
For further information about our Bacterial
Identification and Genotyping software, please download a
copy of our brochure
0.30 MB MIN.pdf
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