PROTEOSTASIS (268285)

  https://cordis.europa.eu/project/id/268285

  FP7 (2007-2013)

  Cell-type-specific modulation of protein homeostasis in health and disease

  Marie Curie Action: "Reintegration Grants" (FP7-PEOPLE-2009-RG)

  proteomics  ·  alzheimer  ·  sensors  ·  homeostasis

  2010-09-01 Start Date (YY-MM-DD)

  2014-08-31 End Date (YY-MM-DD)

  € 100,000 Total Cost

  Description

The correct folding and assembly of proteins and protein complexes is essential to cellular function. Cells have evolved a network of proteins that detect and correct protein damage to maintain proteome health. However, many protein-misfolding diseases, including Huntington’s and Alzheimer’s diseases, are characterized by the accumulation of damaged proteins with devastating consequences for protein homeostasis (proteostasis), resulting in a collection of deleterious phenotypes and affecting many processes. Given that protein expression is cell-type specific, the proteins affected across different cell types are expected to vary. If this is in fact true, then the protein expression profile of a cell will have a profound impact on the folding capacity of its proteins in health and disease. The objective of this project is to determine how cellular proteostasis is adjusted in a cell-specific manner. To this end, I will combine several complementary approaches to compare proteostasis network interactions in different cell types of Caenorhabditis elegans. I will begin by using fluorescent sensors that enable a real-time assessment of proteostasis in a living organism to identify sensor interaction with the proteostasis network in muscle cells. I will then perform cross-tissue analyses of sensor interactions with the proteostasis networks in neuronal and intestinal cells. Finally, I will examine how the chronic expression of misfolded proteins influences sensor interactions with the proteostasis network. This approach will allow me to examine how protein interactions with the cellular proteostasis machinery are changed in response to an altered cellular environment and to determine how the resources of proteostasis are distributed in health and disease. I believe that the proposed research will have broad implications for elucidating the dynamics and limitations of the cellular proteostasis network in a living organism, with long-term implications for therapeutics.

  Complicit Organisations

1 Israeli organisation participates in PROTEOSTASIS.