A5066777904- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- Heat shock proteins research
- RNA Research and Splicing
- Cardiomyopathy and Myosin Studies
- Cardiovascular Function and Risk Factors
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Cardiac Fibrosis and Remodeling
- Calpain Protease Function and Regulation
- Signaling Pathways in Disease
- RNA regulation and disease
- Cardiovascular Effects of Exercise
- Protein Kinase Regulation and GTPase Signaling
- Pancreatic function and diabetes
- SARS-CoV-2 and COVID-19 Research
- S100 Proteins and Annexins
- Genetic Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Genetics, Aging, and Longevity in Model Organisms
- RNA and protein synthesis mechanisms
German Centre for Cardiovascular Research
2015-2024
Heidelberg University
2013-2024
University Hospital Heidelberg
2013-2024
University of Arizona
2021-2024
University of Phoenix
2023-2024
Phoenix (United States)
2021-2024
Discovery Institute
2016-2023
Sanford Burnham Prebys Medical Discovery Institute
2016-2023
Heidelberg University
2021
San Diego State University
2009-2020
Rationale: Endoplasmic reticulum (ER) stress causes the accumulation of misfolded proteins in ER, activating transcription factor, ATF6 (activating factor 6 alpha), which induces ER response genes. Myocardial ischemia response; however, neither function this nor whether it is mediated by known. Objective: Here, we examined effects blocking ATF6-mediated on ischemia/reperfusion (I/R) cardiac myocytes and mouse hearts. Methods Results: Knockdown subjected to I/R increased reactive oxygen...
The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to protect cells from stress-induced cell death before and after its secretion; however, the conditions under which it is secreted are not known. Accordingly, we examined mechanism of MANF release cultured ventricular myocytes HeLa cells, both secrete proteins via constitutive pathway. Although secretion pathway known increase upon changes in intracellular calcium, was...
Stresses that perturb the folding of nascent endoplasmic reticulum (ER) proteins activate ER stress response. Upon stress, ER-associated ATF6 is cleaved; resulting active cytosolic fragment translocates to nucleus, binds response elements (ERSEs), and induces genes, including ER-targeted chaperone, GRP78. Recent studies showed nutrient oxygen starvation during tissue ischemia induce certain GRP78; however, role in mediating this induction has not been examined. In current study, simulating...
The mechanistic target of rapamycin (mTOR) comprises 2 structurally distinct multiprotein complexes, mTOR complexes 1 and (mTORC1 mTORC2). Deregulation signaling occurs during contributes to the severity myocardial damage from ischemic heart disease. However, relative roles mTORC1 versus mTORC2 in pathogenesis are unknown.Combined pharmacological molecular approaches were used alter balance cultured cardiac myocytes mouse hearts subjected conditions that mimic importance protection was...
Hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (Hrd1) is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER quality control by ER-associated (ERAD) of misfolded proteins accumulate during stress. Neither Hrd1 nor ERAD the heart, or cardiac myocytes, critical for proper heart function.The objective this study were elucidate roles stress, ERAD, and viability cultured myocytes mouse vivo.The effects small...
Rationale: Endoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating factor 6α), an inducer of genes that enhance protein folding and restore proteostasis. Because increased synthesis, it is possible proteostasis are challenged during cardiac myocyte growth. However, not known whether activated, if so, what its function hypertrophic growth myocytes. Objective: To examine activity hypertrophy. Methods Results: We found were...
Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition mTORC1 activation. Among regulatory binding partners, the role Proline Rich AKT Substrate 40 kDa (PRAS40) in controlling activity and growth response to pathological physiological stress heart has never been addressed. This report shows PRAS40 cardiomyocytes that AKT-driven phosphorylation relieves inhibitory function PRAS40. overexpression vitro...
Abstract Diabetes is a multi‐organ disease and diabetic cardiomyopathy can result in heart failure, which leading cause of morbidity mortality patients. In the liver, insulin resistance contributes to hyperglycaemia hyperlipidaemia, further worsens metabolic profile. Defects mTOR signalling are believed contribute dysfunctions liver hearts, but evidence missing that activation causal development cardiomyopathy. This study shows specific mTORC1 inhibition by PRAS40 prevents phenotype was...
Rationale: Gene expression profiles have been mainly determined by analysis of transcript abundance. However, these analyses cannot capture posttranscriptional gene control at the level translation, which is a key step in regulation expression, as evidenced fact that levels often poorly correlate with protein levels. Furthermore, genome-wide profiling distinct cell types challenging due to lysates from tissues always represent mixture cells. Objectives: This study aimed develop new...
Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is evolving rapidly. Recently, second-generation CRISPR/Cas9 activation systems based on nuclease inactive dead (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs regulatory regions of any gene interest, enhance transcription. The application dCas9 activate cardiomyocyte transcription in targeted genomic loci vivo has not been demonstrated so far.
Rationale: Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on phosphorylation status involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in myocardium, intracellular mechanism for temporal regulation duration intensity remains obscure. In nonmyocyte context, control folding, activity, stability proteins is mediated by prolyl isomerase Pin1, but role Pin1 heart unknown. Objective:...
We have previously demonstrated that ischemia/reperfusion (I/R) impairs endoplasmic reticulum (ER)-based protein folding in the heart and thereby activates an unfolded response sensor effector, activated transcription factor 6α (ATF6). ATF6 then induces mesencephalic astrocyte-derived neurotrophic (MANF), ER-resident with no known structural homologs unclear ER function. To determine MANF's function vivo, here we developed a cardiomyocyte-specific MANF-knockdown mouse model. MANF knockdown...
ER stress leads to upregulation of multiple folding and quality control components, known as the unfolded protein response (UPR). Glucose Regulated Protein 78 (GRP78) (also binding immunoglobulin protein, BiP, HSPA5) GRP94 are often upregulated coordinately part this homeostatic response. Given that endoplasmic reticulum (ER) chaperones have distinct sets clients, we asked how cells respond ablation individual chaperones. The cellular responses silencing GRP94, HSP47, PDIA6 OS-9, were...
RNA-binding proteins (RBPs) control critical aspects of cardiomyocyte function, but the repertoire active RBPs in cardiomyocytes during growth response is largely unknown. We define healthy and diseased at a system-wide level by RNA interactome capture. This identifies 67 cardiomyocyte-specific RBPs, including several contractile proteins. Furthermore, we identify cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) as dynamic RBP, regulating cardiac both vitro vivo. mRNAs bound to...
Article4 October 2021Open Access Source DataTransparent process Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling Agnieszka A Górska orcid.org/0000-0003-4667-6690 Department of Cardiology, Angiology Pneumology, University Hospital Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), partner site, Heidelberg/Mannheim, These authors contributed equally to this work Search more papers author Clara Sandmann...
Article30 August 2019Open Access Source DataTransparent process TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation Andrea Grund Department for Cardiology Angiology, Hannover Medical School, Hannover, Germany of Cardiovascular Research, European Center Angioscience (ECAS), Faculty Mannheim, University Heidelberg, Search more papers this author Malgorzata Szaroszyk Mortimer Korf-Klingebiel Mona Malek Mohammadi Felix A Trogisch Ulrike Schrameck Anna Gigina...
The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the stressor thapsigargin (TG), which depletes calcium, induced death cultured neonatal rat ventricular (NRVMs) in high media volume but fostered protection low volume. contrast, another stressor, tunicamycin (TM), a glycosylation inhibitor, NRVM all volumes, suggesting that protective proteins were secreted response to TG TM. Proteomic analyses TG- and TM-conditioned showed most was...