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Cooperability
| Project leader |
Banfic Hrvoje |
| Project co-leader: |
Antonio Bedalov |
| Administering organization: |
School of Medicine, University of Zagreb, Salata 3, 10 000 Zagreb, Croatia |
| Partner Institution/Company: |
Fred Hutchinson Cancer Research Center, Seattle, US |
| Grant type: |
1B |
| Project title: |
Chemical genetic approach to identifying inhibitors of nuclear lipid signaling |
| Project summary: |
Signaling pathways involving phosphoinositide 3-kinase (PI-3K) and phosphoinositide (PI) cycle are the most frequently targeted signaling pathways in human cancer. In addition to the signaling events at the cell membrane, the PI cycle is known to occur in nuclei and to regulate important nuclear events, including transcription, mRNA export and telomere length. The major progress in understanding the functional role of the nuclear phospholipid pathway has been recently made by genetic and biochemical studies in the budding yeast Sacharomyces cerevisiae. The aim of this proposal is to develop cell-based assays using heterologous expression of kinases involved in the endonuclear phospholipid signaling in the unicellular eukaryote, S. cerevisiae. In addition, yeast model will be used to dissect the role of particular kinases, especially phospholipase C and PI-3Ks, in regulation of principal and evolutionary conserved nuclear processes. The main hypothesis is that the expression of human proteins in yeasts will induce growth interference and thus provide a yeast cell-based assay to positively screen pharmaceutical agents. The ultimate goal is to be able to identify new, selective small molecule inhibitors of the phospholipid signaling pathway that should provide new opportunities for mechanism-based anticancer therapies. This goal will be achieved by collaborative efforts of two experienced scientists; the project leader from Croatia, who is an expert in the field of the nuclear phospholipid signaling, and Croatian co-applicant from USA, who is an expert in yeast genetics with great experience in using yeast-based positive screen for anticancer drug discovery. |
| Hrvatski sažetak: |
Jedni od najčešće mutiranih gena u ljudskim tumorima su geni koji nose uputu za sintezu enzima koji razgrađuju fosfolipide stanične membrane i tako stanici prenose signale koje potiču njezinu diobu, rast ili diferencijaciju. Podrobnosti fosfolipidnog signalog puta u jezgri ljudskih stanica su samo djelimice opisane, ali su nedavna biokemijska istraživanja u modelu pupajućeg kvasca pokazala da enzimi imaju ulogu u regulaciji ključnih procesa u jezgri, kao što su prepisavanje gena ili duljina kromosoma. Istraživanje uloge jezgrinih enzima koji potiču razgradnju fosfolipida je znatno otežano manjkom specifičnih farmakoloških inhibitora.
Cilj ovoga projekta je otkrivanje specifičnih inhibitora fosfolipidnog puta s pomoću modela u kojemu su ljudski geni koji nose uputu za sintezu enzima fosfolipidnog signalnog puta izraženi u stanicama jednostaničnog pupajućeg kvasca. Takve stanice kvasca se zaustavljaju u rastu, a dodatak potencijalnih inhibitora potiče njihov rast, što predstavlja izvrsni model za otkrivanje specifičnih inhibitora koji nemaju nespecifični, toksični učinak na stanice. Uz istraživanje uloge fosfolipidnog staničnog puta u modelu kvasca i ljudskih stanica, ovo predloženo temeljno znanstveno istraživanje može otkriti nove, molekularno ciljane, „pametne“ lijekove.
Cilj ovoga projekta ostvarit će se zajedničkim radom hrvatskih istraživača u domovini i inozemstvu. Istraživač koji radi Hrvatskoj je stručnjak u području fosfolipidnog signaliziranja u jezgri, a istraživač koji radi u SAD je stručnjak za genetiku kvasca s velikim iskustvom u uporabi modela kvasca za otkrivanje novih lijekova.
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| Amount requested from UKF: |
165 580 € |
| Amount of matching funding: |
19 500 € |
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