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G-protein Coupled Receptors (GPCRs) and Inflammation: From Basic Mechanisms to Clinical Correlates

The overall goal with our research is to understand GPCR activation and signaling in health and disease. The receptor specific ligands identified in combination with the mechanistic insights obtained should help us design GPCR-based therapeutics to modulate inflammation in disease situations. Phagocyte function and inflammatory process are highly regulated by a large group of seven transmembrane GPCRs. These include the ones recognize microbial patterns as well as ”danger signals”, formyl peptides (FPRs), free fatty acids (FFARs), and the ATP receptor (P2Y2R) as well as classic chemoattractant receptors such as platelet activating factor receptor (PAFR), complement fragment 5 receptor (C5aR) and interleukin 8 receptor (CXCR1/2). Many GPCRs in particular the FPRs have been suggested to be of major importance for the initiation and resolution of inflammation, despite this, the precise mechanism of GPCR regulation in inflammation is still not yet understood. To approach GPCRs in health and disease, we focus on the following three specific projects:

  1. 1. GPCR ligand recognition in phagocytes. We have during the last 10 year period identified and characterized a number of different GPCR ligands (agonists, antagonists, and allosteric modulators) belonging to different chemical classes ranging from small compounds, pepducins to the proteolytic stable peptidomimetics. The screening work is still ongoing and the identified receptor specific ligands are subjected for further mechanistic study, structure-activity relationship study, and medicinal chemistry optimization for improved potency as well as bioactivity.
  2. GPCR biased signaling and functional selectivity. Biased signaling is an emerging concept in the GPCR field. We focus on the biased signaling regulated by the actin cytoskeleton, G-protein, as well as beta arrestin downstream neutrophil GPCRs. The identified biased agonism and their downstream signaling pathway leading to a selective functional response in phagocytes will be studied.
  3. GPCR-mediated phagocyte function in health and disease. These studies are performed on both blood and tissue phagocytes obtained from patients suffering from various inflammatory disorders and patients with primary immunodeficiency diseases with well-defined genetic defects. The GPCR- and phagocyte-based assay platform is applied to monitor cell signaling and functions.
Huamei Forsman

Kontaktinformation

Huamei Forsman

Box 480, 405 30 Göteborg

Besöksadress:
Guldhedsgatan 10A, plan 2 , 413 46 Göteborg

Telefon:
+46 31 342 1000

Sidansvarig: kommunikation@medicine.gu.se|Sidan uppdaterades: 2017-06-02
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