A5078072795- Cardiac Fibrosis and Remodeling
- Congenital heart defects research
- Tissue Engineering and Regenerative Medicine
- Genetic Associations and Epidemiology
- Cardiomyopathy and Myosin Studies
- Birth, Development, and Health
- Signaling Pathways in Disease
- Hippo pathway signaling and YAP/TAZ
- Cardiac Structural Anomalies and Repair
- RNA Research and Splicing
- Renin-Angiotensin System Studies
- Cardiac Valve Diseases and Treatments
- Cardiac Ischemia and Reperfusion
- Renal Diseases and Glomerulopathies
- Cardiovascular Function and Risk Factors
- Connective Tissue Growth Factor Research
- Congenital Heart Disease Studies
- Coronary Artery Anomalies
- Hormonal Regulation and Hypertension
- Pluripotent Stem Cells Research
- Chronic Kidney Disease and Diabetes
- Toxin Mechanisms and Immunotoxins
- Cardiovascular Effects of Exercise
- Genetic and Kidney Cyst Diseases
- Genetic Syndromes and Imprinting
Medical College of Wisconsin
2013-2024
Harvard University
2013-2017
Harvard Stem Cell Institute
2014-2017
Brigham and Women's Hospital
2013-2015
University of Minnesota
2015
Minneapolis Heart Institute Foundation
2015
Massachusetts Institute of Technology
2014
Center for Human Genetics
2010-2012
Rationale: Neonatal mice have the capacity to regenerate their hearts in response injury, but this potential is lost after first week of life. The transcriptional changes that underpin mammalian cardiac regeneration not been fully characterized at molecular level. Objective: objectives our study were determine whether myocytes revert phenotype a less differentiated state during and systematically interrogate data identify validate regulators process. Methods Results: We derived core...
Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative genes that contribute overall susceptibility at a single locus. However, majority current lack statistical power test whether underlie same locus, prompting us adopt an alternative approach testing empirically. We used...
Somatic polyploidization, an adaptation by which cells increase their DNA content to support growth, is observed in many cell types, including cardiomyocytes. Although polyploidization believed be beneficial, progression a polyploid state often accompanied loss of proliferative capacity. Recent work suggests that genetics heavily influence cardiomyocyte ploidy. However, the developmental course cardiomyocytes reach final ploidy has only been investigated select backgrounds. Here, we assessed...
Genome-wide association studies (GWAS) identify regions of the genome correlated with disease risk but are restricted in their ability to underlying causative mechanism(s). Thus, GWAS useful “roadmaps” that require functional analysis establish genetic and mechanistic structure a particular locus. Unfortunately, direct testing humans is limited, demonstrating need for complementary approaches. Here we used an integrated approach combining zebrafish, rat, human data interrogate function...
Significance We demonstrate that hearts lacking the sarcomere protein cardiac myosin binding C (MYBPC) undergo altered development due to an extra round of postnatal cell division. Normal myocytes replicate rapidly during fetal life, a final division shortly after birth, cease dividing, and increase in size prepubescent life. MYBPC has unexpected function—inhibition myocyte cytokinesis. MYBPC-deficient additional cytokinesis, resulting increased numbers greater proportion mononuclear...
There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated activity of neonatal CMs vitro. However, events occur downstream role CM proliferation regeneration vivo not been explored. Here, we tested promoting heart investigated pathway(s) specifically CMs. Compared with control, from knockout (IL-13 −/− ) mice showed decreased proliferative...
Abstract Aims The Hippo signalling pathway regulates multiple cellular processes during organ development and maintenance by modulating activity of the transcriptional cofactor Yap. Core components this are required for neonatal mouse heart regeneration, however, investigations to date have typically focused on expression in cardiomyocytes. Due regenerative capacity zebrafish fact that global loss Yap is not fully embryonic lethal zebrafish, we leveraged a yap null mutant investigate impact...
Runx1 is sufficient but not required for cardiomyocyte cell cycle.
Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case SH2B adaptor protein 3 (SH2B3), which a negative regulator of multiple cytokine signaling pathways and associated with increased risk myocardial infarction (MI), its role in post-MI inflammation fibrosis completely unknown.Using an experimental model MI (left anterior descending artery occlusion/reperfusion injury)...
Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating progression. The literature suggests an important role for activation of interleukin-13 interleukin-4 signaling improving ischemic outcomes after myocardial infarction mice. Dupilumab, neutralizing antibody that inhibits shared IL13/IL4 receptor subunit IL4Rα, widely used conditions such as ectopic dermatitis...
Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed using a series of overlapping Dahl salt-sensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb SS 12 (13.4-19.5 Mb) onto consomic SS-12BN background significantly elevated 1% NaCl (146±6 versus 127±1 mm Hg; P<0.001) 8% diets (178±7 144±2 P<0.001). Compared with consomic, these animals also had...
There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 neonatal heart regeneration; however, the cell types mediating regeneration and extent of adult injury are unknown. We identified an abundant source related cytokine, IL-4, type 2 innate lymphoid cells, but this phenomenon declined precipitously hearts. Moreover, receptor deletion macrophages impaired function resulted...
Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset severity disease. We report here for first time ARPKD susceptibility is attenuated by introgressing mutated Pkhd1 allele from (PCK) rat onto FHH (Fawn-Hooded Hypertensive) background. Compared with PCK, FHH.Pkhd1 strain had significantly decreased renal cyst formation coincided a threefold reduction in mean weights. Further analysis revealed FHH. protected...
Background Cardiac fibrosis complicates SARS‐CoV‐2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress‐inducible chaperone that regulates biosynthesis secretion procollagen heart tissue, with the goal elucidating molecular mechanisms underlying cardiac subjects this viral infection. Methods Results Using human autopsy immunofluorescence, immunohistochemistry, quantified Hsp47 + cells...
Many lines of evidence demonstrate that genetic variability contributes to chronic kidney disease susceptibility in humans as well rodent models. Little progress has been made discovering causal genes mainly due complexity. Here, we use a minimal congenic mapping strategy the FHH (fawn hooded hypertensive) rat identify Sorcs1 novel renal candidate gene. We investigated hypothesis variation influences both and human. is expressed kidney, knocking out this gene strain with sensitized genome...
ABSTRACT The Hippo-Yap pathway regulates multiple cellular processes in response to mechanical and other stimuli. In Drosophila, the polarity protein Lethal (2) giant larvae [L(2)gl], negatively Hippo-mediated transcriptional output. However, vertebrates, little is known about its homolog Llgl1. Here, we define a novel role for vertebrate Llgl1 regulating Yap stability cardiomyocytes, which impacts heart development. contrast of Drosophila L(2)gl, depletion cultured rat cardiomyocytes...