Project description:To analyze expression of inflammatory cytokines in Exhaled Breath Condensates from pediatric patients with sickle cell disease, asthma, sickle cell disease and asthma, and controls
Project description:Polymorphonuclear neutrophils are key actors in the pathophysiology of sickle cell disease, but specific factors underlying their activation and sustained inflammation are not well documented. In the present study, we investigated the proteome of neutrophils by a label-free global comparative approach between 4 non-treated sickle patients (SS genotype) at steady state and 4 healthy donors. We identified 101 proteins differentially expressed in SS and normal neutrophils. We found overexpression of CD64 and under-expression of CD62L suggestive of an activated and aged neutrophil profile in SS patients. Comparison of the two proteomes revealed a strong involvement of the type 1 interferon (IFN) response pathway with a 3- to 84-fold increase of type 1 IFN-induced proteins in SS neutrophils, and overexpression of STAT1 and STAT2. Thus, we next determined the plasmatic concentration of type 1 IFNs (IFNα and IFNβ) using the digital-ELISA technology and found a significant higher concentration of IFNα in the plasma from half of our SS patients compared to controls. Overall, a dramatic high-level expression of IFNα signaling proteins in neutrophils from SS patients suggests auto-inflammatory-like phenotype in sickle cell disease at steady state. This finding could open the way to new anti-inflammatory therapies.
Project description:Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. However, pharmacologic induction of fetal hemoglobin sufficient to diminish clinical severity in sickle patients has been challenging. We recently found that up-regulation of PGC-1α can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecular compound SR-18292 increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells or β-YAC and sickle cell disease mice. Sickled red blood cells are significantly reduced and disease complications are alleviated in SR-18292-treated sickle mice. SR-18292, or agents in its class, could be a promising therapeutic for sickle cell disease.
Project description:Circulating platelets from Sickle cell disease (SCD) patients express distinct gene expression patterns that regulate function. The objective of this study is to identify a role of post-transcriptional regulation of the platelet transcriptional signaling by microRNAs. Comparison of microRNA expression in platelets from SCD patients and control subjects, from 2 cohorts-University of Pittsburgh and National Institutes of Health.
