A5002670202- Cardiomyopathy and Myosin Studies
- Congenital heart defects research
- RNA Research and Splicing
- Congenital Heart Disease Studies
- RNA modifications and cancer
- Cardiac Fibrosis and Remodeling
- Muscle Physiology and Disorders
- RNA and protein synthesis mechanisms
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Mitochondrial Function and Pathology
- Single-cell and spatial transcriptomics
- Tissue Engineering and Regenerative Medicine
- Cardiovascular Effects of Exercise
- Genomic variations and chromosomal abnormalities
- Genomics and Rare Diseases
- Neurogenetic and Muscular Disorders Research
- Signaling Pathways in Disease
- ATP Synthase and ATPases Research
- Prenatal Screening and Diagnostics
- Cardiac Valve Diseases and Treatments
- Endoplasmic Reticulum Stress and Disease
- Nuclear Structure and Function
Harvard University
2016-2025
Northwestern University
2022
Brigham and Women's Hospital
2007-2020
Washington Center
2018
University of Washington
2018
Abbott Northwestern Hospital
2015
Zero to Three
2015
Harvard University Press
2010-2014
Howard Hughes Medical Institute
2005-2010
Lakeridge Health
2010
Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly combination immunotherapy. We report the cases of two patients melanoma in whom fatal myocarditis developed after treatment ipilimumab and nivolumab. In both patients, there was development myositis rhabdomyolysis, early progressive refractory cardiac electrical instability, a robust presence T-cell macrophage infiltrates....
Abstract Cardiovascular disease is the leading cause of death worldwide. Advanced insights into mechanisms and therapeutic strategies require a deeper understanding molecular processes involved in healthy heart. Knowledge full repertoire cardiac cells their gene expression profiles fundamental first step this endeavour. Here, using state-of-the-art analyses large-scale single-cell single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight...
Unexplained left ventricular hypertrophy often prompts the diagnosis of hypertrophic cardiomyopathy, a sarcomere-protein gene disorder. Because mutations in for AMP-activated protein kinase gamma2 (PRKAG2) cause an accumulation cardiac glycogen and that mimics we hypothesized cardiomyopathy might also be clinically misdiagnosed patients with other genes regulating metabolism.Genetic analyses performed 75 consecutive unrelated detected 40 mutations. In remaining 35 patients, PRKAG2,...
Powering down yields a healthier heart In hypertrophic cardiomyopathy (HCM), the muscle enlarges and becomes progressively less efficient at pumping blood. HCM can be caused by mutations in components of sarcomere (the heart's contractile unit), most notably myosin. Hypercontractility is among earliest disturbances seen mice carrying these myosin mutations, implying that inflict their damage increasing myosin's power production. Green et al. identified small molecule binds to inhibits its...
Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are most common genetic cause for dilated cardiomyopathy (DCM), a major of heart failure and premature death. Here we show cardiac microtissues engineered from human induced pluripotent stem (iPS) cells powerful system evaluating pathogenicity gene variants. We found certain missense mutations, like TTNtvs, diminish contractile performance pathogenic. By combining functional analyses with RNA...
Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that gene mutations activate proliferative profibrotic signals non-myocyte cells to produce pathologic remodeling HCM. Gene expression analyses of isolated from HCM mouse hearts showed increased levels RNAs encoding cell-cycle proteins, Tgf-β, periostin, other proteins. Markedly BrdU labeling,...
Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of intrinsic force, velocity, ATPase activity myosin have not provided a consistent mechanism to link mutations muscle pathology. An alternative model posits that affect stability sequestered, super relaxed state (SRX) with very slow ATP hydrolysis thereby change number heads accessible actin. Here we show purified exists partly an...
Background: Cancer therapy–induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in genes contribute Methods: studied 213 patients CCM from 3 cohorts: retrospectively recruited adults diverse cancers (n=99), prospectively phenotyped breast cancer (n=73), children acute myeloid leukemia (n=41)....
Mutations in MYBPC3 disrupt myosin states of relaxation, and manipulating therapeutically abates the effects mutations.
Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized transcriptome 880,000 nuclei from 18 control 61 failing, nonischemic human hearts with pathogenic DCM ACM or idiopathic disease. We performed genotype-stratified analyses ventricular cell lineages transcriptional states. The resultant atlas demonstrated distinct...
Abstract Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e) potent Cas9 nuclease delivered by AAV9—to prevent disease mice carrying the heterozygous HCM variant R403Q. One dose of dual-AAV9 vectors, each one half RNA-guided ABE8e, corrected ≥70%...
Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function other cardiac cell types understudied. In this study, we used an isogenic pair BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate role hiPSC-derived fibroblasts (CFs). Analysis type-specific conditional knockout engineered heart tissues revealed essential contribution CF...
We describe a sensitive mRNA profiling technology, PMAGE (for “polony multiplex analysis of gene expression”), which detects messenger RNAs (mRNAs) as rare one transcript per three cells. incorporates an improved ligation-based method to sequence 14-nucleotide tags derived from individual molecules. One tag each molecule is amplified onto separate 1-micrometer bead, denoted polymerase colony or polony, and about 5 million polonies are arrayed in flow cell for parallel sequencing. Using...
Congenital heart disease (CHD) occurs in ∼1% of newborns. CHD arises from many distinct etiologies, ranging genetic or genomic variation to exposure teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between risk factors responses, we compiled integrated comprehensive datasets studies humans model organisms. We examined two alternative models potential functional genes these datasets: direct convergence,...
Abstract PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification patient-derived stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18 , while most tumors without are sensitive. In response PARPi, facilitates ATR activation by interacting with and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous...
Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts DCM overt heart failure (HF) using a genetic model (phospholamban missense mutation, PLNR9C/+). Pre-DCM were phenotypically normal yet displayed proliferation nonmyocytes (59% relative increase vs. WT, P = 8 × 10-4) activation proinflammatory with notable cardiomyocyte-specific...
Aberrant organ development is associated with a wide spectrum of disorders, from schizophrenia to congenital heart disease, but systems-level insight into the underlying processes very limited. Using morphogenesis as general model for dissecting functional architecture development, we combined detailed phenotype information deleterious mutations in 255 genes high-confidence experimental interactome data, and coupled results thorough validation. Hereby, made first systematic analysis...
RNA-seq is a method for studying the transcriptome of cells or tissues by massively parallel sequencing tens millions short DNA fragments. However, broad dynamic range gene expression levels, which span more than five orders magnitude, necessitates considerable over-sequencing to characterize low-abundance RNAs at sufficient depth. Here, we describe that enables efficient normalizing reducing spanned most abundant RNA species least species. This normalization achieved using an approach was...
ABSTRACT Loss-of-function and certain missense mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) significantly decrease or increase bone mass, respectively. These human skeletal phenotypes have been recapitulated mice harboring Lrp5 knockout knock-in mutations. We hypothesized that measuring mRNA expression diaphyseal from with wild-type (Lrp5+/+), (Lrp5–/–), high mass (HBM)-causing (Lrp5p.A214V/+) alleles could identify genes pathways regulate are...
AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show activating PRKAG2 increase microtissue twitch force enhancing myocyte survival. Integrating RNA sequencing metabolomics, remodeled global...
Significance Sequence variants that create or eliminate splice sites are often clinically classified as of unknown significance (VUS) due to imperfect understanding RNA signals and cumbersome functional assays. In autosomal dominant disorders caused by haploinsufficiency, alter normal splicing one allele pathogenic. We developed enhanced computational tools prioritize potential splice-altering VUS used a minigene assay functionally confirm sequence variants. studying all reported across LMNA...