Identifying genes and pathways that drive molecular switches and back-up mechanisms between apoptosis and autophagy

Ziel

A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.

Wissenschaftliches Gebiet

Finanzierungsplan

ERC-AG - ERC Advanced Grant

Gastgebende Einrichtung

WEIZMANN INSTITUTE OF SCIENCE

EU-Beitrag

€ 2 500 000,00

Adresse

HERZL STREET 234
7610001 Rehovot
Israel

Aktivitätstyp

Higher or Secondary Education Establishments

Hauptforscher

Adi Kimchi (Prof.)

Kontakt Verwaltung

Gabi Bernstein (Ms.)

Links

Die Organisation kontaktieren Website

Gesamtkosten

Keine Daten

Begünstigte (1)