Project description:Knowledge about the nature and timepoint of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis (ALS) is largely lacking. It could not only pave the way for valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs (miRNAs) are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained expression profiles of miRNAs as well as other non-coding RNAs (ncRNAs) in the serum of sporadic ALS patients (sALS), familial ALS cases (fALS), asymptomatic mutation carriers and healthy controls. We observed a strikingly homogenous ncRNA profile in fALS patients that, to a large extend, was independent to the underlying disease gene and different to heterogeneous ncRNA signatures in sALS patients. Moreover, we identified 68 significantly dysregulated ncRNAs in pre-manifest ALS mutation carriers, more than 20 years before the estimated time window of disease onset. 91% of ncRNA alterations in mutation carriers overlapped with the fALS patients revealing progressive changes towards and during the disease. Our data thus demonstrate a high epigenetic heterogeneity amongst sALS patients and suggest common denominators regarding molecular pathogenesis of different ALS genes. We describe the earliest pathomolecular alterations in ALS known to date, which provide a basis for the development of predictors of disease onset as well as the discovery of novel therapeutic targets and strongly argue for studies evaluating pre-symptomatic disease-modifying treatment in ALS. Serum ncRNA pofiles of sporadic and familiar ALS patients as well as asymptomatic ALS mutation carriers were compared to age and gender matched healthy controls using a total of 53 Affymetrix miRNA 3.0 arrays. In detail, a total of 9 fALS patients (analyzed in 6 arrays) were compared to 10 controls, a total of 18 ALS mutation carriers (analyzed in 12 arrays) were compared to 8 controls and 18 sALS patients were compared to 16 controls.

Project description:The exact role of epigenetics in the pathogenesis of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is unclear. Herein we have hypothesized that viral micro RNAs (miRNAs) may modulate host cellular and immune responses which may lead to varied clinical presentations. Using bioinformatics tools, we have first predicted putative miRNAs in the genotype of the SARS-CoV-2 and their potential gene targets. Thereafter, quantification of mRNA of key genes regulating inflammation, coagulation, neuropsychiatric functions, fibrosis and glucose metabolism was evaluated in the peripheral blood mononuclear cells and bone marrow of patients suffering from different severities of SARS-CoV-2 infection. Key genes regulating innate immunity, lymphopoiesis, T-cell and B-cell development, cytokine storm, coagulation pathways, fibrosis, neuropsychiatric manifestations, glucose metabolism, and olfaction were significantly downregulated in severe infection when compared with mild infection. Downregulated genes mRNA recovered to normal/near normal levels on recovery from infection. SARS-CoV-2 miRNAs appear promising players in the pathogenesis of COVID-19. Strategies silencing these miRNAs may be explored further as potential therapeutic targets. Patients with severe illness were defined as: respiratory rate ≥30 per min or SpO2 <90% in ambient air, or acute respiratory distress syndrome or septic shock and those with mild illness as: patients with any of the symptoms like fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, but no dyspnea, or abnormal chest imaging. There were 4 severe SARS CoV-2 patients, Median age 57.5 years (Range 50-72 years), all males, median disease duration 7.5 days, duration of hospital stay 38 days with outcome as 3 deaths and one Post covid lung fibrosis. All 4 mild cases had median age 55.5 years (range 42-0 years), 3 males and one female, mean disease duration 2.8 days, mean duration of hospitalization 14.5 days and all recovered. Median age of all 4 recovered cases was 59 years (range 43-77 years), 3 males and one female, mean disease duration of 6 days, mean disease duration of 22 days and all recovered. There were 4 healthy subjects with median age 50 years (range 42-54 years) and there were 3 males and one female. All 3 patients who underwent bone marrow examination had severe Covid-19 and were different then the ones whose peripheral blood was analyed by qRT-PCR. Amongst Disease control subjects (n=3) who underwent bone marrow examination, two had adult onset immune thrombocytopenia and one had a suspicion of myelodysplastic syndrome which was reported to be normal.

Project description:The exact role of epigenetics in the pathogenesis of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is unclear. Herein we have hypothesized that viral micro RNAs (miRNAs) may modulate host cellular and immune responses which may lead to varied clinical presentations. Using bioinformatics tools, we have first predicted putative miRNAs in the genotype of the SARS-CoV-2 and their potential gene targets. Thereafter, quantification of mRNA of key genes regulating inflammation, coagulation, neuropsychiatric functions, fibrosis and glucose metabolism was evaluated in the peripheral blood mononuclear cells and bone marrow of patients suffering from different severities of SARS-CoV-2 infection. Key genes regulating innate immunity, lymphopoiesis, T-cell and B-cell development, cytokine storm, coagulation pathways, fibrosis, neuropsychiatric manifestations, glucose metabolism, and olfaction were significantly downregulated in severe infection when compared with mild infection. Downregulated genes mRNA recovered to normal/near normal levels on recovery from infection. SARS-CoV-2 miRNAs appear promising players in the pathogenesis of COVID-19. Strategies silencing these miRNAs may be explored further as potential therapeutic targets. Patients with severe illness were defined as: respiratory rate ≥30 per min or SpO2 <90% in ambient air, or acute respiratory distress syndrome or septic shock and those with mild illness as: patients with any of the symptoms like fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, but no dyspnea, or abnormal chest imaging. There were 4 severe SARS CoV-2 patients, Median age 57.5 years (Range 50-72 years), all males, median disease duration 7.5 days, duration of hospital stay 38 days with outcome as 3 deaths and one Post covid lung fibrosis. All 4 mild cases had median age 55.5 years (range 42-0 years), 3 males and one female, mean disease duration 2.8 days, mean duration of hospitalization 14.5 days and all recovered. Median age of all 4 recovered cases was 59 years (range 43-77 years), 3 males and one female, mean disease duration of 6 days, mean disease duration of 22 days and all recovered. There were 4 healthy subjects with median age 50 years (range 42-54 years) and there were 3 males and one female.

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Establishing mRNA and miRNA interactions driving disease heterogeneity in ALS patient survival (miRNA-Seq)

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