MTORC IN MYELINATION · The functions of mTOR complex subunits Rictor and Raptor in myelination
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2011-01-01 → 2013-07-31
- Финансиране от ЕС
- 174 065 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеините Raptor и Rictor се изследва чрез проследяване на образуването на миелиновата обвивка при мишки. Разбирането на тези процеси помага при търсенето на терапии за заболявания като рассеяна склероза и периферни невропатии.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The functions of mTOR complex subunits Rictor and Raptor in myelination
Myelination of axons allows rapid propagation of action potentials along the nerve, and is essential for normal function of the nervous system. Diseases affecting myelinating cells, like multiple sclerosis and peripheral neuropathies, have to date very limited forms of treatment. Thus, understanding the molecular basis of myelination is of fundamental importance to provide the foundation for therapeutic solutions to these disabling diseases. Mammalian target of rapamycin (mTOR) is a central regulator of cell growth and metabolism, and is intimately linked with PI3K-Akt signaling. The PI3K-Akt pathway on the other hand is a major player involved in myelination, integrating critical signals mainly from growth factors and the extra-cellular environment. However, very little is known about the role of mTOR signaling in regulating Schwann cell biology and myelination in the PNS. In this project, we have been examining the functional role of mTOR signaling in PNS myelination by conditionally deleting Raptor or Rictor (critical subunits of the two mTOR-containing complexes mTORC1 and mTORC2, respectively) in developing Schwann cells, with the objective to mechanistically understand how mTOR signalling is regulating myelination. We have analysed nerves from mice at different time points of development to morphologically and biochemically determine how deficient mTOR signalling affects myelination. We have furthermore carried out in vitro analysis on primary rat Schwann cells to complement our in vivo findings. Our analysis shows that nerves lacking Raptor have impaired myelination, both during development and in regeneration after injury. Our results also show that signalling pathways downstream of mTOR are severely affected in our knock-out mice, resulting in defective myelin. Our results are now being prepared for publication.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Understanding the molecular basis of myelination, and the nature of the cells that achieve myelination, is of fundamental importance for both basic and clinical neuroscience. Detailed insights into these processes are likely to provide the foundation for therapeutic approaches to diseases affecting myelinating cells, like Multiple sclerosis in the central nervous system (CNS) and Peripheral Neuropathies in the peripheral nervous system (PNS). The host lab has shown that integrin-mediated signals derived from the extracellular matrix together with growth factor signaling via tyrosine kinase receptors are critical for the correct development of myelinating cells and their interaction with neurons. Particularly critical signals integrators are ILK (integrin-linked kinase), as well as the small RhoGTPases Rac1 and Cdc42. Complementary lines of research point to a connected critical role of the PI3K/Akt pathway. The two mTOR-containing complexes 1 (mTORC1) and 2 (mTORC2) are major regulators of these signaling pathways. In this project, we will examine the functional role of mTORC1 and mTORC2 in the development of myelinating cells and during remyelination after injury. To achieve these goals we will use conditional floxed alleles in the mouse that target two critical subunits of the mTOR complexes, raptor (mTORC1) and rictor (mTORC2). These mice are already available in the host laboratory. Using well established Cre recombinase expressing mouse strains, we will eliminate rictor and raptor individually and in combination specifically in developing Schwann cells in the PNS, as well as in mature Schwann cells followed by peripheral nerve injury. If time allows, we will perform complementary experiments in the CNS, using oligodendrocyte-specific gene knock out mice. The work will be embedded in ongoing work in the host laboratory examining the functional role of mTORC1 and mTORC2 in neural stem cell lineage decisions.
Оригинален текст от CORDIS (на английски).
Участници
- EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH · ZuerichКоординаторШвейцария
Връзки
Данни: CORDIS, © Европейски съюз