Dissect cargo selectivity in autophagy

Introduction

(Macro)autophagy is an evolutionarily conserved catabolic process induced to preserve cellular homeostasis under conditions of stress, such as nutrient starvation. Upon autophagy activation, cellular components are engulfed by autophagic vesicles, which then fuse with lysosomes for substrate degradation.

Background

Despite the unquestionable physiological and medical relevance of nutrient- and pharmacological-induction of autophagy in human health, the precise identity of autophagy substrates and the rules governing their selection in vivo are largely unknown.

Objectives

AUTO-SELECT’s goal is to provide a framework to identify physiologically relevant autophagy substrates in different organs and to determine the signaling events that govern their selection. This proposal relies on:

1. Newly generated mouse models to genetically manipulate autophagy and key autophagy regulators.
2. Tools to quantitatively measure autophagy substrate delivery to lysosomes and subsequent degradation in vivo.
3. -omic technologies and bioinformatic tools to dissect the molecular events that govern substrate selection in response to diverse stimulations in a tissue-specific manner.

Therapeutic Applications

In addition, AUTO-SELECT will develop new strategies to modulate selective autophagy and test their therapeutic relevance in connective tissue disorders characterized by the intracellular accumulation of misfolded procollagen molecules.

Potential Impact

AUTO-SELECT has the potential to discover new rules governing cargo selectivity during autophagy and, hence, to provide new links between energy metabolism and cellular quality control that might be exploited for autophagy modulation to treat human diseases.