SMART · Small Molecule Antagonists of chromatin modifying enzymes for Regulation of Transcription, proliferation and differentiation
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2008-08-01 → 2011-07-31
- Финансиране от ЕС
- 229 666 €
- Участници
- 1
- Схема
- MC-IOF
Линиите свързват координатора с партньорите.
Накратко на български
Молекулни проби се използват за промяна на ензимите, които регулират хроматина, например за стимулиране на секрецията на инсулин в панкреасните клетки. Това помага за по-доброто разбиране на процесите на клетъчно делене и развитие при рак и диабет.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Small Molecule Antagonists of chromatin modifying enzymes for Regulation of Transcription, proliferation and differentiation
Executive summary The project aimed at the generation of small molecular probes targeting histone-modifying enzymes and using them, together with functional genomics, to study the role of chromatin in cellular proliferation and differentiation. These goals were pursued in model systems for transdifferentiation towards insulin producing beta cells and for proliferation control of cancer cells. The project was carried out at the Broad Institute of Harvard and the Massachusetts Institute of Technology (MIT) (Boston, United States of America, advisor Stuart Schreiber) and CeMM (Vienna, Austria, advisor Giulio Superti-Furga). The key achievements during the project were: - four primary research articles; - presentation of work at eight conferences and lectures; - two years at the Broad Institute of Harvard and MIT followed by one year of knowledge transfer for the establishment of the CeMM screening platform; - high-throughput screening for histone demethylase inhibitors and the development of methylstat as the first specific demethylase inhibitor; - identification and characterisation of BRD7389 as a small molecular inducer of insulin secretion in pancreatic beta cells; - characterisation of 44 chromatin-targeted compounds for their effects on gene expression in pancreatic alpha and beta cells. In summary, this Marie Curie International Outgoing Fellowship project has not only been successful scientifically, but has also enabled the knowledge transfer from a premier United States research institute to Europe, and provided a path to scientific independence for the research fellow.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Chromatin modifying enzymes play important roles in the regulation of gene expression, the establishment and maintenance of distinct cell types during development and the control of cellular proliferation. All of these features make them interesting targets for small molecule inhibitors that can function as probes for basic biological questions but also as lead compounds for drug development. Indeed the first compounds inhibiting histone deacetylases and DNA methyltransferases have been approved for treatment of proliferative disorders. For other equally important classes of chromatin modifying enzymes, in particular histone methyltransferases (HMTases) and histone demethylases (HDMs), currently only few or no small molecule antagonists are available. Here we propose to identify and generate such compounds and test them together with RNAi libraries for their ability to control cell fate decisions and proliferation in two important medical areas, diabetes and cancer. In diabetes therapy, reestablishment of pancreatic beta cell mass is an important clinical goal. We will address the contribution of chromatin modifying enzymes to beta cell proliferation and trans(differentiation) into beta cells, and then use this knowledge to generate and improve small molecules targeting these pathways. While inducers of proliferation are desirable for beta cell expansion, proliferation control is essential for treatment of cancer. Different chromatin modifying enzymes have been implicated as tumor suppressor genes and oncogenes, making compounds targeting these enzymes promising for cancer therapy. We will identify inhibitors of proliferation in several cancer cell lines that show increased expression of chromatin modifying enzymes. Furthermore, the genetic and epigenetic contributions to cancer development and the synergism between signaling and chromatin modification pathways will be addressed in leukemia cells overexpressing Bcr-Abl.
Оригинален текст от CORDIS (на английски).
Участници
- CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienКоординаторАвстрия
Връзки
Данни: CORDIS, © Европейски съюз