FP7 MARIE CURIE INITIAL TRAINING NETWORK

Control of metabolic and inflamatory pathways by nuclear receptors

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The general objective of this proposal is to understand the pathogenesis of “metaflammation” (metabolic disorders linked to inflammation), through studying the mechanisms by which Nuclear Receptors (NRs) regulate gene expression programs in relevant physiological and pathophysiological settings. A multifaceted approach is planned, which is organized under three major overlapping activities.

  1. Studies on the NR-regulated gene networks and epigenetic mechanisms involved in metaflammation.
  2. Studies on the crosstalk between liver-, adipose tissue- and intestine-specific processes in metaflammation.
  3. Studies on the structure and function of NR-coregulator complexes, NR modifications and novel NR ligands.

Work package 1: Studies on the NR-regulated gene networks and epigenetic mechanisms involved in metaflammation.

Objective 1:

  1. Analysis of NRs participating in the network of transcription factors regulating lipid homeostasis
  2. Analysis of the function of coactivators of distinct NRs, such as histone acetyltransferase complexes and histone deacetylases participating in regulating lipid and glucose homeostasis.
  3. Identification of NR posttranslational modifications in different physiological conditions.

Objective 2:

Functions of the GPS2-containing corepressor complexes in mediating crosstalk between metaflammatory disease pathways.

Objective 3:

  1. Analysis of Nuclear Receptors participating in the network of transcription factors regulating lipid homeostasis and inflammatory responses in macrophages and dendritic cells.
  2. Identification of NR binding sites and interactions with cytokine signaling.

Work package 2: Studies on the crosstalk between liver-, adipose tissue- and intestine-specific processes in metaflammation.

Objective 1:

Elucidating the links between adipose tissue endocrine activity, systemic inflammation and metabolic syndrome.

Objective 2:

Role of nuclear receptor coactivator PGC-1b in the gut-liver axis

Work package 3: Studies on the structure and function of NR-coregulator complexes, NR modifications and novel NR ligands.

Objective 1:

Role of post-translational NR modifications in anti-inflammation

Objective 2:

The regulatory role in vivo of Inositol-1,4,5,6-tetraphosphate in co-repression complexes and biophysical studies of human mutations of nuclear receptors

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