JCSMR - STRATEGIC PLAN

HEALTH THROUGH BASIC DISCOVERY

The emphasis of the School's research will be an understanding of the fundamental principles of human life processes and the pathologies of these processes which cause human disease.

The next ten years will be the decade of integrating genomics with medicine, with the raw sequencing of the human and mouse genomes completed. The genomes of many important human infections have also been sequenced, such as the bacterial agent of tuberculosis. The impact of these developments on medical research is two-fold. First, insight into the genes and molecules that guide health processes is catalysing a breakdown of traditional medical research disciplines, as researchers studying yeast, neuroscience, cancer, and immunology find that they are studying closely related molecules. Second, translating sequence information on genes into advances in understanding and treating human health and disease processes requires multidisciplinary skills, core tools, and facilities that are beyond the reach of individual research groups or departments. The depth of expertise and unique core facilities in the School, and its close links with other research groups in the University, the Clinical School, CMHR, NCEPH, and CSIRO, have strategically placed the School to meet these challenges and lead the integration of genomics, gene regulation and signalling, immunity, neuroscience and physiology, in the Australian and world scene.

The School will undertake basic research in the core areas of

Genomics

Immunity

Gene regulation and cell signalling

Neuroscience and Integrative Physiology

These fundamental investigations will be relevant to understanding many human diseases. However, the School will be well placed to make important contributions to the understanding and treatment of

Infectious diseases
Diabetes
Cancer
Asthma
High blood pressure

While research in the core areas listed above will be the focus of the School's research, the School will only have sufficient resources to fund activities in selected topics from these fields.

GENOMICS

In the 21st century the direction of biomedicine will be dominated by the genomics revolution. Knowledge of all the genes in an organism's genome, and their patterns of variation and expression is becoming a necessary basis for biomedical research. An integrative approach to understanding the complexity of whole biological systems is superseding the study of isolated components-the research paradigm of the second part of the last century. Disparate research areas, such as yeast molecular biology, evolutionary genetics, physiology and clinical oncology, are becoming intimately connected and reciprocally informative. For the first time there is the promise of unravelling the development and functioning of complex systems such as the brain and the immune system, and of whole organisms. There is also the very real prospect of understanding how biological processes are involved in complicated diseases such as cancer, mental illness and diabetes. The School will play a significant role in this new intellectual environment. Existing strengths in genomics and bioinformatics will be developed. They will facilitate synergistic interactions, forming the basis for integration of all the School's research activities.

IMMUNITY

Advances in genomics, protein structure, gene expression and cell signalling are opening tremendous opportunities to understand how immunity is regulated in health and disease, and to develop new ways to combat infectious disease, asthma, autoimmune diseases such as diabetes, and cancer. The School has a rich tradition in illuminating basic mechanisms of immunity, exemplified by the Nobel prize-winning discovery of MHC restriction, and a breadth and depth of expertise in integrating genes, structure and signals with immune physiology and with development of new therapeutics and vaccines. The School is positioned to be Australia's strongest multidisciplinary research team in the field of immunology, with world-leading expertise ranging from mouse genomics, immune cell signalling and gene expression, small and large animal models of infection, immune cell tumours and autoimmunity, to design and phase I clinical testing of novel vaccines and anti-inflammatory small molecules.

CELL SIGNALLING AND GENE REGULATION

Understanding how cells process, integrate and interpret the complex signals to which they are exposed is a key to understanding how an organism views and responds to its environment during growth and development. For example cells of the immune system are constantly bombarded with new pathogenic or environmental signals with which they have to deal. The brain and neuronal network also have to interpret the complex environment of the organism. The intracellular signalling network that responds to outside signals is made up of many interacting multiprotein complexes that send signals to the cell nucleus to change patterns of gene expression. While the major advances in whole genome sequencing will provide information on the sequences of all the proteins involved in these processes, the next major challenge will be to understand the dynamics and structure of the many large protein that are responsible for intracellular signalling and gene expression. The current advances in genomics, microarray technology, proteomics and intracellular imaging means that it is now possible to meet this major challenge. A global view of gene expression patterns can now be obtained at both the RNA (microarrays) and protein level (mass spectrometry). Structures of protein complexes can be solved (X-ray crystallography and cryo-electron microscopy) and real time images of intracellular processes can be obtained (multiphoton microscopy). A detailed understanding of the complex signalling events that lead to altered patterns of gene expression will provide many targets for the design of novel drugs for diseases where aberrant signalling or gene expression plays a role.

NEUROSCIENCE AND INTEGRATIVE PHYSIOLOGY

One of the great scientific challenges for future generations will be to understand how our brains perform sensory, motor and cognitive tasks and control body haemostasis. The need to understand brain pathologies is more pressing, as their social and economical impact is usually long-term. Apart from injuries, many brain pathologies arise from developmental abnormalities, genetic predispositions, environmental factors or unknown aetiologies. Advances in genomics, imaging, cell signalling, protein structure and electrical recording have provided new insights and potential treatments for dementias, motor dysfunction and sensory deficits. The School has a strong tradition in neuroscience, beginning with the Nobel prize-winning discoveries by Eccles on the ionic basis of excitation and inhibition. The School has great research depth in cell signalling within and between neurones. This strength will be used to understand neuronal development, sensory mechanisms, motor control, synaptic plasticity and memory. The research will rely on the use of in vivo and in vitro models, multiphoton imaging combined with electrical recording, and genetically modified animals.

As with neuroscience, there will be a renaissance in in vivo physiology using genetically modified animals. The School has a strong research group working on blood pressure control.

CORE FACILITIES AND SKILL BASE

To ensure that the School realises these research objectives it must ensure that the necessary infrastructure and technologies are provided. These are

The capacity to genetically engineer modified animals, and provide adequate holding facilities for them, to explore links between genes, molecules, cellular events and immunity.
State-of-the-art imaging, allowing imaging of living tissues, cells, cell microdomains, and cell signalling with sub-micron resolution.
Core technologies for genome wide analysis of gene expression and gene polymorphisms.
High-speed cell sorting and analysis by flow cytometry, which is critical for analysing cells from mouse mutants and in signalling and gene expression studies.
The capacity to study the interaction between genetic variants in infectious agents and genetically altered small animals, through small animal biohazard containment facilities.
The technologies and skill base for genome wide analysis of the protein content of cells or subcellular structures using proteomics approaches such as mass spectrometry coupled with bioinformatics approaches to data analysis.
Re-establishment of in vivo recording and monitoring techniques.
Maintenance of a skilled workshop staff, with expertise in fine instrumentation and electronic design.
Access to expertise in mouse behavioural studies.
Expertise in bioinformatics, including new areas of mathematics, statistics and computer science.

The School must attract or retain staff with state-of-the-art expertise in key technological areas, such as genomics, bioinformatics, biomolecule production, protein structure and proteomics, signalling, imaging, cell biology and cell sorting; and in key application areas of immunity such as small animal models of important infectious diseases, asthma and allergy, autoimmune diseases, and the immunology of cancer. The School must also foster the clinical delivery of this process, by building resources, collaborative links and in-house expertise in hospital-based genetic epidemiology and family studies of infectious diseases, autoimmune diseases, and asthma, and with commercially-based efforts to develop and trial new vaccines and therapeutics.

JCSMR WITHIN THE ANU

There are many synergies between the research outlined in this plan, and the research activities of other Schools and Departments. The School anticipates that there will be many opportunities to interact and share infrastructure in the field of genomics, proteomics, bioinformatics and advanced imaging.

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