PGC-1α Agonism Induces Fetal Hemoglobin and Exerts Anti-Sickling Effects in Sickle Cell Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1079787 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28073200.fastq.gz | Fastqsanger.gz | |||
| SRR28073201.fastq.gz | Fastqsanger.gz | |||
| SRR28073202.fastq.gz | Fastqsanger.gz | |||
| SRR28073203.fastq.gz | Fastqsanger.gz | |||
| SRR28073204.fastq.gz | Fastqsanger.gz |
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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.
2024-08-08 | GSE256494 | GEO
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. Additional pharmacologic agents to induce sufficient fetal hemoglobin to diminish clinical severity is an unmet medical need. We recently found that up-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecule, SR-18292, increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells, β-globin yeast artificial chromosome mice, and sickle cell disease mice. In SR-18292-treated sickle mice, sickled red blood cells are significantly reduced, and disease complications are alleviated. SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.
| S-EPMC11290485 | biostudies-literature
Project description:The heterozygous inheritance of the sickle cell gene, called sickle cell trait (HbAS), was previously thought to be benign. HbAS is now associated with an increased risk for chronic kidney disease, pulmonary embolisms, and exertional rhabdomyolysis. The role of gene expression, as regulated by microRNAs, in these clinical HbAS associations has not been investigated. We explored the association between HbAS and the differential expression of circultaing (plasma) microRNAs when compared to the normal hemoglobin phenotype (HbAA). In stark contrast, the homozygous inheritance of the sickle cell gene, called sickle cell anemia (HbSS) is a severe disease that was previously associated with early mortality and severe morbidity. With appropriate care and early interventions, people with HbSS have improved life expectancy but still experience significant morbidity including cardiac, kidney, and pulmonary disease. The role of gene expression as regulated by microRNA in these clinical HbSS associations has not been investigated. We also explored whether the presence of HbSS is associated with the differential expression of circultaing (plasma) microRNAs as compared to the normal hemoglobin phenotype (HbAA).
2025-03-22 | GSE285580 | GEO
Project description:Sickle cell disease (SCD) is caused by a pathogenic hemoglobin (Hb) mutation, yet patients can have dramatically variable clinical manifestations. Here we address the genetic basis of this clinical heterogeneity. Using a systems genetics approach, we performed whole blood gene expression analysis and eQTL analysis on different clinical phenotypes in SCD patients. We generated whole blood gene expression profiles for 311 West-African children recruited from the National Sickle Cell Disease Centre in Cotonou, Benin which included 250 patients with varying degrees of SCD severities and 61 age-matched controls. SCD is caused by a point-mutation in the beta-hemoglobin gene that changes the normal HbAA protein into, most often, an abnormal HbSS or HbSC protein. The SCD patients recruited in the study either had HbSS or HbSC phenotypes and were categorized into different 3 clinical states based on follow-up status (Rahimy, MC, et al. Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in sub-Saharan African setting. Bood 102, 834-838. 2002). When patients are refered to the clinic, they are enrolled when they are in steady-state condition, and are labeled as entry (E). Patients followed at the SCD clinic are labeled as FU. Control patients were recruited and are labeled as C. Patients were also assigned a severity score (Sebastiani, P. et al. A network model to predict the risk of death in sickle cell disease. Blood 110, 2727-2735, 2007). Hemoglobin protein status (Hb phenotype) was confirmed for each patient using standard electrophoretic techniques. We generated genotypes for 263 of these individuals and performed principal component analysis (PCA) which identified 2 signigicant genotypic principal components (gPC1 and gPC2). Using the gene expression and genotyping data, we performed an eSNP analysis. . Gene expression data presented in this study.
2014-07-01 | E-GEOD-35007 | biostudies-arrayexpress
Project description:MicroRNA (miRNA) molecules hold promise as potential therapeutics capable of silencing target gene expression through RNA interference. The delivery of miRNAs without degradation has posed a significant challenge to their clinical use. However, cholesterol-conjugated miRNA has emerged as a promising delivery approach thanks to its low toxicity and high efficiency. We previously showed that MIR29B by 28-day continuous infusion using subcutaneous mini osmotic pump delivery, MIR29B induces HbF. The present study delves into evaluating intermittent delivery of a cholesterol-conjugate of MIR29B (Chol-MIR29B), to induce fetal hemoglobin (HbF) in Townes sickle cell mice. Therefore, we conducted additional in vivo studies to test intermittent dosing of Chol-MIR29B in Townes sickle cell mice. Blood was processed for complete blood count with differential and reticulocytes at weeks 0, 2, and 4, and γ-globin gene reactivation was determined by RT-qPCR. The percentage of HbF-positive cells was measured by flow cytometry. RNA seq was performed on the peripheral blood of mice treated with MIR29B. Mice treated with Chol-MIR29B exhibited normal behavior and weight gain. While there was no direct effect of Chol-MIR29B on γ-globin reactivation, delivery of Chol-MIR29B after 4 weeks of treatment significantly increased the percentage of HbF positive cells by up to 15-fold. Additionally, there were no toxic effects on complete blood counts and differential or activation of oncogenes as determined by RNA seq, supporting the safety of Chol-MIR29B while inducing HbF expression. Our results provide the first evidence of the ability of Chol-MIR29B to induce HbF in sickle cell disease transgenic mice.
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Project description:We hypothesized that miRNA regulation may be invloved in hydroxyurea-mediated fetal hemoglobin induction. Microarray analysis was utilized as an initial screening tool to determine differential miRNA expression in CD71+ erythroid cells comparing cells from control individuals without sickle cell anemia to patients with sickle cell anemia prior to treatment with hydroxyurea and patients receiving the maximum tolerated dose (MTD) of hydroxurea.
2011-11-21 | GSE32035 | GEO
Project description:We hypothesized that miRNA regulation may be invloved in hydroxyurea-mediated fetal hemoglobin induction. Microarray analysis was utilized as an initial screening tool to determine differential miRNA expression in CD71+ erythroid cells comparing cells from control individuals without sickle cell anemia to patients with sickle cell anemia prior to treatment with hydroxyurea and patients receiving the maximum tolerated dose (MTD) of hydroxurea. CD71+ cells were isolated from whole blood of control individuals (n=2), pediatric patients without hydroxyurea treatment (n=3) and pediatric patients at hydroxyurea MTD (n=3). All 8 samples were analyzed for miRNA expression.
2011-11-21 | E-GEOD-32035 | biostudies-arrayexpress
Project description:The Differential Expression of Circulating MicroRNAs in Sickle Cell Trait and Sickle Cell Anemia compared to the Normal Hemoglobin Phenotype.
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Project description:Sickle cell disease (SCD) is caused by a pathogenic hemoglobin (Hb) mutation, yet patients can have dramatically variable clinical manifestations. Here we address the genetic basis of this clinical heterogeneity. Using a systems genetics approach, we performed whole blood gene expression analysis and eQTL analysis on different clinical phenotypes in SCD patients.
2014-07-01 | GSE35007 | GEO
Project description:Levels of fetal hemoglobin have been associated with differences in severity and outcome of sickle cell disease (SCD). While some genetic associations have been reported between SNPs and HbF level, little of the variance in the trait is explained, and most studies have focused on African American, rather than African samples. We have carried out a GWAS in a collection of SCD patients from Dar es Salaam, Tanzania. This sample represents a diverse, metropolitan collection of individuals from East Africa. Omni 2.5M genotypes and HbF levels (measured after 5 years of age) are available.
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