Obiettivo Life-long blood regeneration is critically dependent on self-renewing multipotential hematopoietic stem cells (HSCs). HSCs’ nearly unlimited self-renewal potential and lifetime persistence in the body, in contrast to the committed progenitors (CP), signifies the need for HSCs genome integrity tight control. Indeed, accumulation of unrepaired DNA damage in HSCs is associated with bone marrow failure and accelerated leukemogenesis. Our recent findings revealed for the first time striking differences in DNA Damage Response (DDR) characteristics between HSCs and CPs isolated from umbilical cord blood. Human HSCs exhibited attenuated DNA repair, persistent DDR signaling and increased apoptosis relative to CPs. Yet, the molecular basis and physiological significance of these HSC-specific DDR characteristics remain unexplored.To bridge the gap in this highly significant knowledge I propose the following research objectives: 1) To analyze in details DDR signaling in the highly purified HSC and CP subsets isolated from physiologically distinct developmental stages of human hematopoiesis: fetal, neonatal and adult; 2) To identify functional regulators engaged by genotoxic stress in normal and leukemia stem cells. To address these questions I will employ multi color flow cytometry, functional genetic screens, mRNA/microRNA expressional profiling, clonal in vitro assays and, most importantly, in vivo repopulation assays of human normal HSC and leukemia-initiating cells. Furthermore, we will pursue a novel DNA repair fluorescent reporter strategy to examine DNA repair activity and fidelity in live human HSC.This original study will form the foundation for my long-term goals of identifying regulators of DDR in human HSCs and in leukemia-initiating cells, revealing mechanisms utilized by self-renewing cells to maintain genome integrity and combat stress, and provide novel insights into leukemogenesis, blood regeneration and aging. Campo scientifico engineering and technologymaterials engineeringcolorsnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologyleukemianatural sciencesbiological sciencesgeneticsgenomes Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Invito a presentare proposte FP7-PEOPLE-2012-CIG Vedi altri progetti per questo bando Meccanismo di finanziamento MC-CIG - Support for training and career development of researcher (CIG) Coordinatore TEL AVIV UNIVERSITY Contributo UE € 100 000,00 Indirizzo RAMAT AVIV 69978 Tel Aviv Israele Mostra sulla mappa Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Lea Pais (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
