Early Detection of Cystic Fibrosis Acute Pulmonary Exacerbations by Exhaled Breath Condensate Metabolomics

The most common cause of death in cystic fibrosis (CF) patients is progressive lung function decline, which is punctuated by acute pulmonary exacerbations (APEs). A major challenge is to discover biomarkers for detecting an oncoming APE and allow for pre-emptive clinical interventions. Metabolic profiling of exhaled breath condensate (EBC) samples collected from CF patients before, during, and after APEs and under stable conditions (n = 210) was performed using ultraperformance liquid chromatography (UPLC) coupled to Orbitrap mass spectrometry (MS). Negative ion mode MS data showed that classification between metabolic profiles from "pre-APE" (pending APE before the CF patient had any signs of illness) and stable CF samples was possible with good sensitivities (85.7 and 89.5%), specificities (88.4 and 84.1%), and accuracies (87.7 and 85.7%) for pediatric and adult patients, respectively. Improved classification performance was achieved by combining positive with negative ion mode data. Discriminant metabolites included two potential biomarkers identified in a previous pilot study: Lactic acid and 4-hydroxycyclohexylcarboxylic acid. Some of the discriminant metabolites had microbial origins, indicating a possible role of bacterial metabolism in APE progression. The results show promise for detecting an oncoming APE using EBC metabolites, thus permitting early intervention to abort such an event.Fil: Zang, Xiaoling. Georgia Institute of Techology; Estados UnidosFil: Monge, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Gaul, David A.. Georgia Institute of Techology; Estados UnidosFil: McCarty, Nael A.. University of Emory; Estados UnidosFil: Stecenko, Arlene. University of Emory; Estados UnidosFil: Fernández, Facundo M.. Georgia Institute of Techology; Estados Unido

Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor’s innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling