A5053565747- Endoplasmic Reticulum Stress and Disease
- Cardiovascular Function and Risk Factors
- Mitochondrial Function and Pathology
- Heat shock proteins research
- Autophagy in Disease and Therapy
- Viral Infectious Diseases and Gene Expression in Insects
- Cardiac Fibrosis and Remodeling
- Genetics, Aging, and Longevity in Model Organisms
- Cardiac electrophysiology and arrhythmias
- CRISPR and Genetic Engineering
- Calpain Protease Function and Regulation
- Cardiac Ischemia and Reperfusion
- Cardiomyopathy and Myosin Studies
- Heart Failure Treatment and Management
- Viral Infections and Immunology Research
- Diabetes Treatment and Management
- Pancreatic function and diabetes
- GDF15 and Related Biomarkers
- Virus-based gene therapy research
- Receptor Mechanisms and Signaling
- Lipid metabolism and disorders
- RNA regulation and disease
- Hormonal Regulation and Hypertension
- Transgenic Plants and Applications
- Adipose Tissue and Metabolism
University of Arizona
2021-2024
Phoenix (United States)
2021-2024
University of Phoenix
2023
San Diego State University
2016-2021
Blackwood
2016-2019
University Hospital Heidelberg
2016
Discovery Institute
2016
German Centre for Cardiovascular Research
2016
Heidelberg University
2016
Sanford Burnham Prebys Medical Discovery Institute
2016
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...
Abstract Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this has not been employed vivo. Here we show, using mouse model myocardial ischemia/reperfusion, that selective pharmacologic the ATF6 arm unfolded protein response (UPR) during reperfusion, typical clinical intervention point after infarction, transcriptionally reprograms proteostasis, ameliorates...
Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated diverse diseases. The small molecule N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (147) was previously identified (<xref ref-type="bibr" rid="bib35">Plate et al., 2016</xref>) preferentially activate the ATF6 arm of UPR, promoting protective remodeling ER network. Here we show that...
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...
Abstract There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B‐like vitamin choline plays key roles in body‐ and brain‐related functions. Choline produced endogenously by phosphatidylethanolamine N‐methyltransferase protein liver not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% Americans do reach recommended intake choline. Thus, it's imperative determine whether...
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...
Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors endoplasmic reticulum (ER) stress response and, as such, it critical for protecting heart other tissues from a variety environmental insults disease states. In heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in cell types are unknown. Here we show that decreases activation fibroblasts cytokine, transforming growth factor β (TGFβ), which can induce fibroblast...
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...
Abstract Genetic manipulation in vivo is a critical method for mechanistically understanding gene function disease and physiological processes. To facilitate this, embryonic transgenesis popular animal models like mice has been developed. Compared to the longer, expensive methods of transgenesis, viral vectors, such as adeno‐associated virus (AAV), have grown increasingly popularity due their relatively low cost ease production, translating an overall greater versatility biological tool. In...
Although peroxisomes have been extensively studied in other cell types, their presence and function gone virtually unexamined cardiac myocytes. Here, neonatal rat ventricular myocytes (NRVM) we showed that several known peroxisomal proteins co-localize to punctate structures with a morphology typical of peroxisomes. Surprisingly, found the protein, fatty acyl-CoA reductase 1 (FAR1), was upregulated by pharmacological pathophysiological ER stress induced tunicamycin (TM) simulated...
Background: Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These can be removed by adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated (ERAD), which, as biological process rate, has not been studied vivo. To investigate role for ERAD pathophysiological model, we examined function functional initiator ERAD, valosin-containing...
We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for selective delivery 147, small molecule ATF6 activator, ischemia/reperfusion injury. ROS-activatable 1 negative control unable to release free drug were synthesized examined peroxide-mediated activation. Prodrug blocks activity 147 by its inability undergo metabolic oxidation ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly first time. Biological in...
The isolation and culturing of cardiac myocytes from mice has been essential for furthering the understanding physiology pathophysiology. While isolating neonatal mouse hearts is relatively straightforward, adult murine heart are preferred. This because compared to cells, more accurately recapitulate cell function as it occurs in vivo. However, technically difficult isolate necessary quantities viability, which contributes an experimental impasse. Furthermore, published procedures specific...
The molecular determinants of lifespan can be examined in animal models with the long-term objective applying what is learned to development strategies enhance longevity humans. Here, we comment on a recent publication examining mechanisms that determine worms, Caenorhabditis elegans (C. elegans), where it was shown inhibiting protein synthesis increased levels transcription factor, ATF4. Gene expression analyses showed ATF4 genes responsible for formation gas, hydrogen sulfide (H2S)....