Laboratory Members

Dr Tom Brodnicki

Laboratory Head
Immunology and Diabetes Unit
St Vincent's Institute

Telephone:+61 3 9288 2502
Facsimile: +61 3 9416 2676
Email: tbrodnicki@svi.edu.au

Education:

Awards:

Scientific Involvement:

• Advisory Panel, Juvenile Diabetes Research Foundation Australia
• Medical and Scientific Review Committee, Juvenile Diabetes Research Foundation International
• Stage 1 reviewer, Challenge Grants, NIH-USA
• Member, American Association for the Advancement of Science
• Member, Australasian Society of Immunology
• Member, Australian Society of Medical Research
• Member, St Vincents Institute Faculty

Research Interests:

My research group is focused on how genetic and environmental factors increase one's risk for developing autoimmune diseases, such as type 1 diabetes. During the course of evolution, it might be assumed that genetic variation conferring susceptibility for autoimmune diseases would undergo negative selection and be removed from the population. One explanation for the continued presence of particular disease genes is that they provide increased resistance to infectious diseases. On the other hand, the hygiene hypothesis suggests that certain childhood infections may temper the immune system and decrease the risk for developing autoimmunity in genetically at-risk individuals. To study this paradox, my group uses a combination of genomic methods, immunological techniques, and mouse models to facilitate the identification of disease genes, as well as determine if bacterial infection can modulate the immune system and prevent autoimmune disease.

Lab Members:

• Colleen Elso, PhD: Peter Doherty Postdoctoral Fellow
• Iris Tan, BScHons: PhD student
• Nancy Wang, BScHons:PhD student
• Michelle Ashton, BScHons: PhD student
• Sean Ivory, BS Honours: student
• Leanne Mackin, BS: Senior Research Assistant

Research Projects :

Genomic and functional analyses of a novel gene implicated in type 1 diabetes

Despite the recent success of human genetic studies for type 1 diabetes (T1D), the contribution of identified genes is often not clear and still requires basic biological studies that are not possible in human patients. An excellent animal model for studying the role of T1D susceptibility genes is the nonobese diabetic (NOD) mouse. Similar to children with T1D, NOD mice develop diabetes due to the destruction of insulin-producing beta cells mediated by autoreactive lymphocytes. We have recently used the NOD mouse strain to discover a previously unknown gene in which sequence variation is associated with T1D. We are currently using a range of molecular and cellular methods, including the generation of a gene knockout mouse strain, to determine the function of this novel gene and its role in T1D pathogenesis.

How does bacterial infection affect susceptibility to type 1 diabetes?

It has been observed that the incidence of autoimmune diseases is escalating in developed countries where infectious diseases have generally decreased. Although hotly debated, the hygiene hypothesis suggests that certain childhood infections may temper the immune system and trigger a protective mechanism against autoimmunity in those individuals who have inherited T1D susceptibility genes. Unfortunately, it is difficult to test this hypothesis in human patients. Instead, laboratory mouse strains can be used to investigate genetic and environmental factors contributing to autoimmune diseases, such as T1D.

We have recently confirmed that the NOD mouse strain, which develops T1D similar to humans, is susceptible to certain bacterial infections. The goal of this project is to determine why NOD mice are more susceptible to these bacterial infections compared to other mouse strains. Furthermore, we aim to test the hypothesis that bacterial infection can alter T1D susceptibility in NOD mice depending on the time and dose of infection. Characterization of the genes and immune cell subsets, which contribute to bacterial susceptibility in NOD mice, may elucidate biological mechanisms that can be targeted to prevent T1D in at-risk individuals.

Accelerating disease gene discovery using transposon mutagenesis

An alternative strategy to traditional genetic mapping studies is to identify those genes that, when disrupted, prevent disease. Such genes may represent new therapeutic targets. While not possible in humans, genetic techniques can be used to disrupt genes in laboratory mouse strains and discover which ones are necessary for disease onset. We aim to implement a relatively new genetic method using a DNA tag, called a transposon, that jumps from one spot to another within the mouse genome and disrupts genes. The advantage of this technique is that when the transposon randomly inserts into a gene, it not only disrupts the gene, but also serves as a tag, making it possible to quickly identify the mutated gene.

We have successfully established transgenic mice that harbor the two components of the transposon system: the transposon DNA tag and the enzyme that catalyzes transposon jumping. To help us identify offspring with gene mutations, we have used a transposon containing a fluorescent marker that results in mice that fluoresce if the transposon has jumped into a gene. A distinct advantage of this system is that disrupted genes can be rapidly identified using the transposon tag and prioritized for analysis of disease-related traits using a range of molecular and cellular methods.

Selected Publications: