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Young Researchers and Professionals
| Project leader |
Nagy Vanja |
| Administering organization: |
Mediterranean Institute for Life Sciences
Mestrovicevo setaliste bb
21000 Split
Croatia
tel: 00385-21-555-602
fax: 00385-21-555-605
http://www.medils.hr
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| Partner Institution/Company: |
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| Grant type: |
3A |
| Project title: |
Regulation of Neurotrophin Receptor Signaling and Endocytosis during Neuronal Development and Plasticity |
| Project summary: |
Summary: Endocytosis of ligand-bound receptor tyrosine kinases (RTKs) is essential to control cellular responses by adjusting the level of receptors at the cell surface as well as defining specificity of signalling pathways inside cells. The signalling endosome containing NGF (nerve growth factor) and BDNF (brain derived neurotrophic growth factor) neurotrophin receptors was shown to be essential for the survival of neurons. Dr. Dikic’s group has recently shown that the ubiquitin ligase, Cbl, and its interacting partners (CIN85/CDAP2) control multiple steps in the endocytosis of RTKs and actin reorganization in neurites. Yet, little is known about their physiological relevance in vivo. The importance of Cbl pathways in retrograde transport and signalling of BDNF and NGF receptor complexes (signalosomes) will be analyzed in transgenic mice deficient for Cbl/Cbl-b and CIN85/CD2AP. These mice will also be used to test whether Cbl-linked pathways control neurite outgrowth during development and neuronal plasticity in adulthood.
Objective: The major goal of this proposal is to study the molecular mechanisms underlying endocytosis of neurotrophin receptors and their physiological importance in development and neuronal plasticity in vivo. In particular, the interaction between intracellular transport and signalling of neurotrophin-receptor signalling complexes (signalosomes) will be analysed.
Biological Significance: Understanding molecular mechanisms underlying synaptic plasticity, the basis of our cognitive abilities, is fundamentally important, since they decline with age, protracted neuropathologies and acute brain injuries. Dr. Dikic and colleagues have described a novel signalling pathway in vitro, which have great implications in central nervous system (CNS) development and maintenance. Classically, neurotrophins and their receptors have only been considered during CNS development, and only recently are being appreciated for their role during normal adult CNS function, such as synaptic activity associated with long-term potentiation (LTP), learning and memory. Thus, very little is known about their function and regulation during these fundamental processes. Here, we propose to elucidate the negative regulation of ligand-bound neurotrophin receptors, during development and adult neural plasticity in vivo. Insight into signalling pathways that might be at play during normal brain development and adult function provides possible novel therapeutic targets, and thus contribute to the overall improvement and quality of human life.
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| Hrvatski sažetak: |
Kontrola neutrofnih receptora i endocitoze tijekom zivcanog razvoja i neuroplasticnosti.
Vanja Nagy. PhD
MedILS, Split
U žiži istraživačkog interesa u laboratoriji prof. Ivana Dikica u MedILS-u je vrlo konzervirana molekula ubikvitin, građena od 76 amino-kiselina koja se kovalentno veže za neke proteine. Vezanje se odvija preko karboksi-terminalnog glicina na ubikvitinu i lizina u ciljnom proteinu. Dodavanje ubikvitina na proteine odvija se u nekoliko koraka, te njegovo dodavanje ima različite učinke na sudbinu proteina, a to onda utječe na različite stanične funkcije. Na primjer, vezanje jednog ubikvitina (monoubikvitinacija) je povezano s endocitozom membranskih proteina, razvrstavanjem proteina u multivezikularna tjelešca, otpuštanje retrovirusa, popravkom DNA oštećenja kao i u regulaciji genske aktivnosti. S druge strane, vezanje više ubikvitina (poliubikvitinacija) preko lizina 48 ima ključnu ulogu u usmjeravanju proteina u proteazom na razgradnju, a vezanje poliubikvitina na lizin 63 potiče endocitozu i popravak DNA. Nadalje, „ubikvitinski put“ je vrlo važan za regulaciju NF?B transkripcijskih čimbenika koji su ključni u regulaciji upalnih procesa. Poremećaj u regulaciji NF?B čimbenika je ključan za razvoj malignih tumora koji nastaju zbog kronične upale (Terzic J et al., Biochem Soc Trans 2007;35:942-5).
Predloženi projekt planira proučiti kako monoubikvitinacija živčanih čimbenika rasta (NGF i BDNF) utječe na njihovu biološku funkciju te razvoj živčanih stanica. Predoženo istraživanje temelji se na otkricu istraživačke grupe prof. dr. I. Đikića (Goethe University u Frankfurtu) u kojemu je pokazano da su proteini Cbl/Cbl-b i CIN85/CD2AP, ključni za monoubikvitinaciju, endocitozu i degradaciju tirozin kinaznih receptora u drugim stanicama. Ovaj projekt ce koristeći transgenične životinje bez jednog gena (engl. knockout) pokusati razjasniti in-vivo funkciju proteina Cbl/Cbl-b u razvoju i funkciji zivcanih stanica.
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| Amount requested from UKF: |
61.000 € |
| Amount of matching funding: |
16.000 € |
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