How do apoptosis and anergy integrate to prevent autoimmune disease?
Project type
PhD
| Supervisor(s) | Division | |
Dr Daniel Gray (Primary) |
Molecular Genetics of Cancer | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Molecular Genetics of Cancer | .(JavaScript must be enabled to view this email address) |
Details of project
Many different mechanisms have been proposed to maintain the property of immunological tolerance. Identifying which of these mechanisms are truly essential to prevent autoimmune disease and how they might be targeted therapeutically to treat autoimmunity is a major question in immunology. In this project, we propose to leverage our insights into deletional tolerance to reveal how the process of lymphocyte anergy safeguards tolerance.
The apoptotic regulator, Bim, is required to prevent autoimmune disease. However, our recent data have shown that functional inactivation (anergy) of autoreactive lymphocytes that evade apoptosis can also preserve tolerance. In this project, we will perform an RNA interference screen in new mouse models with apoptotic defects to discover genes necessary for anergy that cooperate with apoptosis in tolerance. This high throughput in vivo approach will identify disease-relevant targets using next-generation sequencing. These targets will then be tested in a variety of autoimmune-prone mouse models to establish whether they are critical for immunological tolerance.
The RNA interference screen will be complemented with an established mutagenesis program in mice. The mutagen, ethyl nitrosourea (ENU; http://en.wikipedia.org/wiki/ENU) is used to introduce random point mutations throughout the genome. Those mutations that cause autoimmune disease are discovered using next-generation sequencing techniques to reveal novel gene variants involved in tolerance. The twist is that we use mice carrying a Vav-BCL-2 transgene that inhibits apoptosis in all hematopoietic cells and sensitizes the immune system to further defects in tolerance.
Together, these approaches will shed new light how immunological tolerance mechanisms integrate to prevent autoimmune disease and the molecular pathways that we should be targeting therapeutically.
Project references
- Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM and Strasser A. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature. 2002 Feb 21;415(6874):922-6. PMID: 11859372
- Goodnow CC. Multistep pathogenesis of autoimmune disease. Cell. 2007 Jul 13;130(1):25-35. PMID: 18632054
Research interests
The molecular mechanisms of apoptosis are a major research focus of the Molecular Genetics of Cancer division. The importance of these mechanisms to human health is exemplified by how apoptosis shapes the immune system to allow normal immune responses and prevent autoimmunity. Our previous research has revealed those apoptotic pathways critical to immunological tolerance.
Selected publications
- Strasser A. The role of BH3-only proteins in the immune system. Nature Reviews Immunology. 2005 Mar;5(3):189-200. PMID 15719025
- O’Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature. 2009 Oct 1;461(7264):659-63. PMID 19794494
- Bouillet P, O’Reilly LA. CD95, BIM and T cell Homeostasis. Nature Reviews Immunology. 2009 Jul;9(7):514-9. PMID 19543226
Research theme
Chronic inflammatory diseases
Scientific discipline
- Autoimmunity
- Cell Biology
- Immunology
Keywords
Apoptosis