A5071186147- Congenital heart defects research
- Congenital Heart Disease Studies
- Renal and related cancers
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Single-cell and spatial transcriptomics
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- MicroRNA in disease regulation
- Gene expression and cancer classification
- Pluripotent Stem Cells Research
- Genomics and Phylogenetic Studies
- Extracellular vesicles in disease
- Renal cell carcinoma treatment
- Genetic and Kidney Cyst Diseases
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Tracheal and airway disorders
- Coronary Artery Anomalies
- TGF-β signaling in diseases
- Cancer-related molecular mechanisms research
- Aortic Disease and Treatment Approaches
- Cardiovascular Function and Risk Factors
- Pancreatic function and diabetes
University of Pittsburgh
2012-2025
Children's Hospital of Pittsburgh
2019
Developmental Studies Center
2019
Max Planck Institute for Molecular Genetics
2007-2009
Single-cell RNA sequencing (scRNA-seq) technologies enable the study of transcriptional heterogeneity at resolution individual cells and have an increasing impact on biomedical research. However, it is known that these methods sometimes wrongly consider two or more as single cells, a number so-called doublets present in output such experiments. Treating downstream analyses can severely bias study's conclusions, therefore computational strategies for identification are needed.With scds, we...
Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating the established number cardiomyocytes.
Abstract Heart development is a continuous process involving significant remodeling during embryogenesis and neonatal stages. To date, several groups have used single-cell sequencing to characterize the heart transcriptomes but failed capture progression of at most This has left gaps in understanding contribution each cell type across cardiac development. Here, we report transcriptional profile murine from early late Through further analysis this dataset, identify features. We gene...
Abstract Heart organoids have the potential to generate primary heart-like anatomical structures and hold great promise as in vitro models for cardiac disease. However, their properties not yet been fully studied, which hinders wide spread application. Here we report development of differentiation systems ventricular atrial heart organoids, enabling study diseases with chamber defects. We show that our chamber-specific comprising major cell types, use single RNA sequencing together sample...
Background Transforming growth factor beta 1 (TGFβ1) plays a major role in many lung diseases including cancer, pulmonary hypertension, and fibrosis. TGFβ1 activates signal transduction cascade that results the transcriptional regulation of genes nucleus, primarily through DNA-binding transcription SMAD3. The objective this study is to identify genome-wide scale map SMAD3 binding targets molecular pathways networks affected by TGFβ1/SMAD3 signaling epithelial cells. Methodology We combined...
MicroRNAs (miRNAs) are post-transcriptional regulators that bind to their target mRNAs through base complementarity. Predicting miRNA targets is a challenging task and various studies showed existing algorithms suffer from high number of false predictions low moderate overlap in predictions. Until recently, very few considered the dynamic nature interactions, including effect less specific expression level, combinatorial binding. Addressing these issues can result more accurate miRNA:mRNA...
Hypoplastic left heart syndrome (HLHS) is a severe congenital disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, mutations in Sap130, chromatin modifier, Pcdha9, cell adhesion protein, also exhibits mitotic block increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, Sap130 ChIPseq analyses all demonstrate dysregulation of genes autism cognitive impairment. This includes...
The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal controlled by a regulatory network governed factors OCT4, SOX2 NANOG. Recent studies on reprogramming somatic to induced highlight as key regulator pluripotency.We have carried out an integrated analysis high-throughput data (ChIP-on-chip RNAi experiments along with promoter sequence putative target genes)...
ABSTRACT Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), histone deacetylase inhibitor (HDI), as an enhancer recovery, showed PTBA increased RTEC reduced fibrosis. Here, investigated mechanisms in...
Background Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of high prevalence airway ciliary dysfunction (CD; 18/43 or 42%) increased respiratory symptoms. Furthermore, heterotaxy patients were to have more postsurgical pulmonary morbidities. These findings are likely reflection the common role motile cilia in both clearance and patterning. As CHD comprising transposition great arteries...
Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable a three-stage surgical course ending Fontan palliation. However, 10-year transplant-free survival remains at 39-50%, ventricular dysfunction progressing to failure (HF) being common sequela. For SV-CHD patients who develop HF, undergoing the would not be helpful and could even detrimental. As HF risk cannot predicted metabolic defects have been observed in Ohia mice, we hypothesized that...
Abstract Life expectancy continues to increase in the high-income world due advances medical care; however, quality of life declines with increasing age normal aging processes. Current research suggests that various aspects are genetically modulated and thus may be slowed via genetic modification. Here, we show evidence for epigenetic modulation process brain from over 1800 individuals as part Framingham Heart Study. We investigated methylation genes protocadherin (PCDH) clusters, including...
Abstract Motivation Single cell RNA sequencing (scRNA-seq) technologies enable the study of transcriptional heterogeneity at resolution individual cells and have an increasing impact on biomedical research. Specifically, high-throughput approaches that employ micro-fluidics in combination with unique molecular identifiers (UMIs) are capable assaying many thousands per experiment rapidly becoming commonplace. However, it is known these methods sometimes wrongly consider two or more as single...
Bicuspid aortic valve (BAV) with ∼1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in disease and aorta dilation a major cause of adult cardiac surgery. BAV genetically linked to rare left-heart obstructions (left ventricular outflow tract [LVOTOs]), including hypoplastic left syndrome (HLHS) coarctation (CoA). Mouse human studies indicate LVOTO heterogeneous complex genetic etiology. Homozygous mutation Pcdha protocadherin gene cluster mice can BAV,...
DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its binding preferences and downstream-regulatory effects. Experimentally identified TF sites (TFBSs) usually similar enough be summarized 'consensus' motif, representative of the specificity. Studies have shown groups nucleotide TFBS variants (subtypes) can contribute distinct modes downstream regulation via differential recruitment cofactors. A TF(A) may bind subtypes a(1) or a(2)...
Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery a rare dominant lethal mutation TPM1, sarcomeric actin-binding protein, eight individuals with large atrial septal defect (ASD) five-generation pedigree. Mice Tpm1 exhibit early embryonic lethality disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show...
Current methods that annotate conserved transcription factor binding sites in an alignment of two regulatory regions perform the and annotation step separately combine results end. If site descriptions are weak or sequence similarity is low, local gap structure poses a problem detecting sites. It therefore desirable to have approach able simultaneously consider as well possibly matching locations.With SimAnn we developed tool serves exactly this purpose. By combining sequences into one...
The molecular events driving specification of the kidney have been well characterized. However, how initial field size is established, patterned, and proportioned not Lhx1 a transcription factor expressed in pronephric progenitors required for kidney, but few interacting proteins or downstream targets identified. By tandem-affinity purification, we isolated FRY like transcriptional coactivator (Fryl), one two paralogous genes, fryl furry (fry), described vertebrates. Both were found to...
Abstract The kidney is a complex organ composed of more than 30 terminally differentiated cell types that all are required to perform its numerous homeostatic functions. Defects in development significant cause chronic disease children, which can lead failure only be treated by transplant or dialysis. A better understanding molecular mechanisms drive important for designing strategies enhance renal repair and regeneration. In this study, we profiled gene expression the developing mouse at...
Summary Hypoplastic left heart syndrome (HLHS) is a severe congenital defect with 30% mortality from failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed patient iPSC-CM have increased apoptosis, redox stress, failed antioxidant response. This was associated mitochondrial permeability transition pore (mPTP) opening, hyperfusion respiration defects....
ABSTRACT/SUMMARY One million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing failure. Current concepts do not sufficiently address mechanisms failure development specifically for these patients. We show that cardiomyocyte cytokinesis is increased tetralogy Fallot pulmonary stenosis (ToF/PS), common form CHD. Labeling ToF/PS baby isotope-tagged thymidine showed after birth. used single-cell transcriptional profiling to discover underlying...
Introduction: Hypoplastic left heart syndrome (HLHS), a congenital defect involving left-sided structures, is associated with poor neurodevelopmental outcome, >30% experiencing impairment. A mouse model of HLHS showed brain abnormalities, suggesting shared genetic etiology for and cardiac defects in HLHS. Hypothesis: Mutations Sap130 Pcdha9 causing mice may individually or together cause abnormalities neurobehavioral deficits. Methods Results: Confocal histopathology MR imaging was used...