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Pathogenesis of autoimmune neurodegeneration: What causes the immune system to destroy healthy neurons?

Objective

The goal of this research is to determine under which conditions an autoimmune attack on neurons can occur. There is a growing interest in neuroimmunology, and data suggests that disorders such as Parkinson’s disease and schizophrenia have an autoimmune component. The ideal disease for studying this phenomenon is, however, the sleep disorder narcolepsy with cataplexy (NC), where the hypocretin (hcrt) producing neurons in hypothalamus are lost. Genetic and epidemiological evidence suggest that the specific hcrt cell loss is caused by an autoimmune attack, but the trigger of this is unknown. As post doctoral fellow at Stanford Center for Sleep Sciences Dr. Birgitte R. Kornum has been involved in the discovery of two genetic associations in NC. This has implicated the P2Y11 receptor and DNA methyltransferase 1 (DNMT1) in the pathogenesis of NC and warrants further studies of these two proteins and their functions in the immune system and the brain. The overarching aim of the research proposed here is to study autoimmune destruction of neurons, and how P2Y11 and DNMT1 contribute to the pathological process. Autoimmune destruction of neurons is prevented by several mechanisms. Negative selection of autoreactive T cells occurs during T cell maturation in the thymus. This process is, however, far from perfect and T cells with reactivity towards neuronal targets are instead controlled by other less well-understood mechanisms. These include inhibition of T cell activity by regulatory T cells, suppression of MHC expression in mature neurons, and a higher resistance in neurons to apoptotic signals from T cells. The experiments proposed here studies P2Y11 and DNMT1 in these processes using in vitro and in vivo models. Studies of patient samples from the Danish Center for Sleep Medicine will translate basic findings to the clinical situation. Together these studies will answer important questions, not only about NC, but about autoimmunity towards neurons in general.

Field of science

  • /medical and health sciences/clinical medicine/psychiatry/schizophrenia
  • /medical and health sciences/basic medicine/neurology/parkinson
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/psychiatry/sleep disorders

Call for proposal

FP7-PEOPLE-2012-CIG
See other projects for this call

Funding Scheme

MC-CIG - Support for training and career development of researcher (CIG)

Coordinator

REGION HOVEDSTADEN
Address
Kongens Vaenge 2
3400 Hillerod
Denmark
Activity type
Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments)
EU contribution
€ 100 000
Administrative Contact
Per E. Jørgensen (Dr.)