Projects / Programmes
The role of small GTPases in the regulation of endosomal/lysosomal transport in astrocytes
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| B470 |
Biomedical sciences |
Physiology |
| Code |
Science |
Field |
| 3.05 |
Medical and Health Sciences |
Other medical sciences |
glia, astrocyte, endocytosis, endosomes, lysosomes, Rab, GDI, virus klopnega meningitisa
Researchers (17)
Organisations (3)
Abstract
From the initial consideration of being the “brain glue”, astrocytes, the most abundant glial cells in the brain, are today regarded as multifunctional cells implicated in a myriad of processes including the role of integrating and tuning inter-neuronal signalling through the uptake and release of several chemical messengers. The aim of this proposal is to study endocytosis in astrocytes, a mechanism, by which molecules from the extracellular medium and those associated with the plasma membrane enter astrocytes in vesicles (endosomes/lysosomes). Once in these vesicles the luminal material travels to distinct subcellular destinations by mechanisms poorly understood. We will specifically ask whether the mobility of endosomes/lysosomes in astrocytes is regulated by small Rab GTPases, which together with their regulatory and effector proteins (GDI) control the endocytic pathway and vesicle recycling. The understanding of this traffic is relevant for the understanding of process related to cognition, since genes regulating monomeric GTPases were found to be associated with mental retardation. Moreover, endocytosis may be “hijacked” by virus infection and we will study whether viruses utilize the endocytic pathway for their infection. To address these questions we will use the recently developed approaches and methods in our labs, that consist of molecular biology, cell physiology and quantitative microscopy to monitor the mobility of fluorescently labelled vesicles in living cells. All these represent the methods of choice to address these questions. Therefore, we strongly believe that the results of the proposed research are not only novel, but will provide important new insights into the understanding of astrocyte role in physiological and pathological conditions, such as mental retardation and virus infection.
Significance for science
In the focus of our research were astrocytes, the most abundant glial cells in the mammalian brain which have the crucial role for the functioning of neurons. The role of astrocytes was studied from the perspective of the regulation of endocytosis and recycling of membrane bound vesicles. From a growing number of studies in recent years emerged hypotheses about the connection between the impaired vesicle transport in several diseases, especially in the neurodegenerative diseases of the central nervous system (CNS) and cognitive disabilities. Until now the studies were fucused to neurons, the key players in the CNS. On the other hand, astrocytes represent neuronal supportive cells and affect their differentiation and synaptic transsmision. From this point of view it is of outmost importace to study which circumstances affect vesicle trafficking in astrocytes and how is this related to the functioning of neurons. Our research have revealed that endolysosomal transport is impaired in the presence of defective endosomal Rab4 and Rab5 GTPases and their regulatory protein GDI, which mutations were identified in a form of intellecual disability syndrom, a quite common disability. The research represents an important step in the identification of the connections between impairments of endolysosomal transport in astrocytes and irregularities in neuronal functioning and survival. Additionally, the neurotropic viruses that enter cells via endocytotic compartments, can affect cellular processes. Beside neurons they can infect other CNS cells, including astrocytes. In our research, the first of this kind, we monitored the dynamics vesicular changes in TBE infected live astrocytes. We have shown that virus affected the dynamics of endolysosomal movements and at the same time did not affect the survival of rat astrocytes, which places the results in the support of the new paradigm about the rodent brain representing the possible TBE reservoir.
Significance for the country
- Basic scientific research in field of cell phisology helps to highlight the grand picture in the functioning of tissues and organs in the normal physiologic conditions and in human diseases and dysabilities. In also represents the platform for the evolving the improved diagnostics and the development of more specific target drugs. Inovations and drugs are important development steps of every country. - The publishing of the research findings in the outstanding scientific journals with high impact factors and the attendence of international symposia increase the recognition of the University of Ljubljana and in Slovena. - The research in the hot-topic field importantly adds to the educational level of the reseachers in the project group and secondary, also of younger researchers and students. The research project increased the recognisability of the research group members in scientific circles and contributed to the development of further research plans with the recognised international researcher worlwide. This is of outmost importance for increasing the prestige of the reaearch group, their members and the country.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
