Projects / Programmes
Dynamics of lysosomes and antigen presentation by astrocytes
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| B470 |
Biomedical sciences |
Physiology |
reactive astrocytes, autoimmune disorders, lysosomes, intermediate filaments, cytoskeleton, trafficking
Researchers (10)
Organisations (2)
Abstract
Myelin disorders such as multiple sclerosis (MS) form an important group of human neurological diseases that are yet incurable. To initiate the inflammatory cascade, leading to demyelination, T cells have to recognize a specific myelin antigens, which need to be presented in the context of major histocompatibility complex (MHC) class II molecules on the plasma membrane of astrocytes. Astrocytes are the most common glial cells in the central nervous system (CNS) and they can adjust to local inflammation by varying its own expression of MHC class II molecules. MHC class II molecules are synthesized in endoplasmic reticulum and afterwards transferred to lysosomal compartments. Upon receiving an inflammation stimulus astrocytes transform into potent antigen presenting cells by upregulation of lysosomal exocytosis and by the representation of MHC class II molecules, leading to T cell restimulation and demyelination. Reactive astrocytes could therefore play a crucial role in the course of inflammation process in the brain parenchyma by presenting MHC class II molecules on their surface. The mechanism of delivering MHC class II molecules to the plasma membrane is exocytosis of lysosomes. However, the precise mechanism of lysosomal trafficking to the plasma membrane of astrocytes is still unclear. In view of the recent findings that altered cytoskeleton network may alter mobility of different vesicles in the cytoplasm of astrocytes, we aim to investigate whether altered intermediate filament network affects the redistribution of MHC class II molecules to the cell surface in reactive astrocytes. Findings of previous studies allow the assumption that upregulation of intermediate filaments (IFs) may be involved in the astroglial functional shift from neurite-promoting (permissive), to neurite-inhibiting (non-permissive) elements. Therefore, our goal is to determine the phenotype of reactive astrocytes as potential antigen presenting cells and to test the hypothesis that the increase in IFs expression affects the process of representation of MHC class II molecules on the membrane of reactive astrocytes. The trafficking of lysosomes containing MHC class II molecules will be examined in spontaneous and stimulated conditions (calcium, cAMP) in primary astrocyte cell cultures from wild type mice and from knock-out mice deficient of intermediate filaments (GFAP-/-Vim-/-). Characterizing the role of IFs in antigen presentation in CNS will result in a better understanding of the pathological mechanisms involved in MS and may have a significant impact on a development of effective therapies for clinical manifestations.
Significance for science
Neurodegenerative diseases, such as multiple sclerosis, are chronic diseases of the central nervous system in which immune system reactions have been implicated. Recent studies indicate that nervous system resident cells, including astrocytes, play crucial role in inflammation processes. Present therapies are effective to mild the symptoms and possibly slow the disease. Therefore, it is crucial to understand the mechanisms of antigen presentation in astrocytes. The results of this study will importantly contribute to a better understanding of the mechanisms by which inflammatory reactions lead to defects of the central nervous system. A better understanding of the cellular processes by which astrocytes mediate the immune response will allow the design of new pharmacological tools that could improve multiple sclerosis treatment.
Significance for the country
Neurodegenerative diseases such as multiple sclerosis significantly affect the quality of life and consequently the living standards of individual and society. They have an important impact on the standards of living and withdrawal from social activities. Since there is no effective treatment it is crucial to find novel therapeutic or preventive approaches. The present project will not only contribute to these global efforts, but it also contributes to educate young researchers in fundamental research.
Most important scientific results
Annual report
2008,
2009,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
2009,
final report,
complete report on dLib.si
