A5058326657- Cardiomyopathy and Myosin Studies
- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Cardiovascular Effects of Exercise
- Cellular Mechanics and Interactions
- RNA Research and Splicing
- Congenital heart defects research
- Force Microscopy Techniques and Applications
- Neurobiology and Insect Physiology Research
- Monoclonal and Polyclonal Antibodies Research
- Developmental Biology and Gene Regulation
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- Cardiovascular Function and Risk Factors
- Phosphodiesterase function and regulation
- Genetic Neurodegenerative Diseases
- Genetics and Neurodevelopmental Disorders
- Cardiac Fibrosis and Remodeling
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Protein Degradation and Inhibitors
- Metabolism, Diabetes, and Cancer
- BRCA gene mutations in cancer
- Radiomics and Machine Learning in Medical Imaging
University of Arizona
2014-2025
University of Virginia
2001-2023
New York University
1997-2020
University Medical Center
2014
Amsterdam UMC Location Vrije Universiteit Amsterdam
2014
Janelia Research Campus
2013
Heidelberg University
2013
University Hospital Heidelberg
2013
Queen's Medical Centre
2001
New York Medical College
2000
Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of in novel mouse model with genetically altered splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography.Compliant upregulated through deletion RNA...
Objective Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management this important emerging disorder. Methods Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans . We then undertook a detailed analysis the clinical, histopathological imaging features these patients. Results All had prenatal or early onset hypotonia contractures. None...
The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised molecular motor myosin. filament is a precisely controlled length, defining thereby force level that generate how this varies with muscle length. It been speculated mechanism by which length involves giant protein titin, but no conclusive support for hypothesis exists. Here we show in mouse model deleted two titin's C-zone super-repeats, reduced cardiac muscles. In addition,...
Background— Diastolic dysfunction is a poorly understood but clinically pervasive syndrome that characterized by increased diastolic stiffness. Titin the main determinant of cellular passive However, physiological role tandem immunoglobulin (Ig) segment titin plays in stiffness generation and whether shortening this sufficient to cause need be established. Methods Results— We generated mouse model which 9 Ig-like domains (Ig3–Ig11) were deleted from proximal Ig spring region (IG KO). Exon...
Significance Mutations in titin are a major cause of heart failure, yet the functions large parts not understood. Here we studied titin’s I-band/A-band junction that has been proposed to be crucial for thick filament length control. We made mouse which IA was deleted. Super-resolution microscopy (structured illumination microscopy) revealed deleting increases strain on molecular spring elements without altering length. Single cell biomechanical measurements showed this passive stiffness...
Titin, the largest protein known, forms an elastic myofilament in striated muscle sarcomere. To establish titin’s contribution to skeletal passive stiffness, relative that of extracellular matrix, a mouse model was created which molecular spring region shortened by deleting 47 exons, TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts much stiffer titin molecule. Mechanical studies with this novel support is main determinant stiffness. Unexpectedly, vivo sarcomere...
Background The titin gene ( TTN ) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. truncating mutations cause dilated cardiomyopathy DCM ); however, of missense variants has been difficult to elucidate because presence background variation. Methods Results A cohort 147 index subjects underwent DNA sequencing for 313 exons covering N2B N2 BA cardiac isoforms . Of 348 variants, we identified 44 “severe” rare by using...
Nebulin is a giant filamentous protein that coextensive with the actin filaments of skeletal muscle sarcomere. mutations are main cause nemaline myopathy (NEM), typical adult patients having low expression nebulin, yet roles nebulin in remain poorly understood. To establish nebulin's functional muscle, we studied novel conditional KO (Neb cKO) mouse model which deletion was driven by creatine kinase (MCK) promotor. Neb cKO mice born high levels their muscles, but within weeks after birth...
Highlights•The layout of titin's C-zone in relation to MyBP-C is relevant cardiomyopathies but unknown.•Immuno-localization studies showed that cMyBP-C locates near the interface between titin super-repeats.•Interface domains belong two super-repeats are likely involved anchoring cMyBP-C.•Not all super-repeat interfaces equal: 1 and 2 does not localize cMyBP-C.•This study enhances insights molecular its cMyBP-C.AbstractTitin largely comprised serially-linked immunoglobulin (Ig) fibronectin...
TTN (titin) is the third myofilament type of cardiac sarcomere and performs important functions that include generating passive tension. Changes in expression are associated with dysfunction, one main genes linked to dilated cardiomyopathy (DCM). DCM frequently changes N2BA (compliant isoform), 1 2 major isoforms found heart (the other isoform being N2B [stiff isoform]). Whether altered causes or a secondary change remains unclear. Here, we present mouse model, TtnΔ112-158 which specifically...
Background: Low myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure preserved ejection fraction. Cyclic monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression reported to be upregulated human fraction myocardium chronic administration of a inhibitor reverses preestablished cardiac hypertrophy systolic dysfunction mice subjected...
Co-activation of Meisl with Hoxa7 or Hoxa9 homeobox genes by retroviral gene insertion has recently been reported to be leukemogenic in murine myeloid leukemia. In this study we determined their expression human Most leukemia cell lines co-expressed MEIS1 HOXA7 and HOXA9. Among patients acute leukemia, 50% AML expressed MEIS1, while the majority ALL were negative. A total 89.5% expressing HOXA7. unadjusted models, poorer response chemotherapy was associated regardless status older more...
Titin is a molecular spring that determines the passive stiffness of muscle cells. Changes in titin's occur various myopathies, but whether these are cause or an effect disease unknown. We studied novel mouse model which was slightly increased by deleting nine immunoglobulin (Ig)-like domains from constitutively expressed proximal tandem Ig segment (IG KO). KO mice displayed mild kyphosis, phenotype commonly associated with skeletal myopathy. Slow muscles were atrophic alterations myosin...
Nebulin rules thin-filament length in fast skeletal muscle but collaborates with leiomodin-2 muscles optimized for efficiency.
Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector-mediated transfer mice indicated cardiac toxicity associated with ectopic expression of transgene. Here, we performed preliminary dose study severe double-knockout mouse model deficient and dysferlin. We evaluated safety biodistribution AAV9-desmin-hCAPN3 vector administration to nonhuman...
Titin is a large filamentous protein that forms sarcomeric myofilament with molecular spring region develops force in stretched sarcomeres. The has complex make-up includes the N2A element. This element largely consists of 104 residue unique sequence (N2A-Us), flanked by immunoglobulin domains (I80 and I81). interest because it assembles signalosome CARP (Cardiac Ankyrin Repeat Protein) as an important component; both interacts N2A-Us I81 highly upregulated response to mechanical stress....
Abstract Nebulin is a giant protein that winds around the actin filaments in skeletal muscle sarcomere. Compound-heterozygous mutations nebulin gene ( NEB ) cause typical nemaline myopathy (NM), disorder characterized by weakness with limited treatment options. We created mouse model missense mutation p.Ser6366Ile and deletion of exon 55, Compound-Het resembles NM. show mice are growth-retarded have weakness. Muscles reduced myofibrillar fractional-area sarcomeres disorganized, contain rod...
As the only class I helix-loop-helix transcription factor in Drosophila, Daughterless (Da) has generally been regarded as a ubiquitously expressed binding partner for other developmentally regulated bHLH factors. From analysis of novel tissue-specific allele, dalyh, we show that da expression is not constitutive, but dynamically regulated. This transcriptional regulation includes somatic ovary-specific activation, autoregulation and negative regulation. Unexpectedly, diverse functions may...
During Drosophila oogenesis two distinct stem cell populations produce either germline cysts or the somatic cells that surround each cyst and separate formed follicle. From analyzing daughterless (da) loss-of-function, overexpression genetic interaction phenotypes, we have identified several specific requirements for da+ in during follicle formation. First, da is a critical regulator of proliferation. Also, required complete differentiation polar stalk cells, elevated levels can even drive...