A5066216029- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Circadian rhythm and melatonin
- Folate and B Vitamins Research
- Muscle metabolism and nutrition
- RNA Research and Splicing
- Pancreatic and Hepatic Oncology Research
- Acute Lymphoblastic Leukemia research
- Liver Disease Diagnosis and Treatment
- Mitochondrial Function and Pathology
- Fibroblast Growth Factor Research
- Metabolomics and Mass Spectrometry Studies
- Polyamine Metabolism and Applications
- Biochemical Acid Research Studies
- CRISPR and Genetic Engineering
- Neurobiology and Insect Physiology Research
- PI3K/AKT/mTOR signaling in cancer
- Pancreatitis Pathology and Treatment
- Nutrition and Health in Aging
- Autophagy in Disease and Therapy
- RNA and protein synthesis mechanisms
- Diet and metabolism studies
- Genetics, Aging, and Longevity in Model Organisms
Rutgers Sexual and Reproductive Health and Rights
2019-2025
Rutgers, The State University of New Jersey
2015-2024
Rütgers (Germany)
2022
University of Pennsylvania
2012-2014
Cancer Research Institute
2012-2014
Disturbances in protein folding and membrane compositions the endoplasmic reticulum (ER) elicit unfolded response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, ATF6-is activated by ER stress. PERK phosphorylation eIF2 represses global synthesis, lowering influx nascent polypeptides into stressed ER, coincident with preferential translation ATF4 (CREB2). In cultured cells, induces transcriptional expression genes directed arm UPR, including involved amino acid...
A stress adaptation pathway termed the integrated response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that eIF2 kinase GCN2 is required for sustained growth androgen-sensitive and castration-resistant models of PCa both vitro vivo, patient samples. Using RNA-seq transcriptome analysis a CRISPR-based phenotypic screen, was shown regulate expression over 60 solute-carrier ( SLC ) genes, those involved amino acid transport loss function...
Amino acid availability is sensed by GCN2 (general control nonderepressible 2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal transduction events remains mysterious. In this study we utilized mouse genetic models to investigate the role in hepatic mTORC1 regulation upon amino stress induced a single injection asparaginase. We found that deletion Gcn2 prevented phosphorylation eukaryotic initiation factor 2α asparaginase...
Abstract Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation amino acids. Halofuginone (HF) is a potent inhibitor aminoacylation tRNAPro with broad biomedical applications. Here, we show that in addition translational control directed by activation ISR general nonderepressible 2 (GCN2), HF increased free acids translation genes involved protein biogenesis via sustained signaling. Deletion GCN2 reduced survival...
Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation recycling 1 . In adult mice, autophagy sustains metabolism prevent wasting by cachexia survive fasting, also suppresses inflammation, liver steatosis, neurodegeneration, lethality 2,3 Defects in contribute metabolic, inflammatory degenerative diseases, however, the specific mechanisms involved were unclear 4 Here we profiled inflammation mice with conditional, whole-body...
The antileukemic agent asparaginase triggers the amino acid response (AAR) in liver by activating eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible (GCN2). To explore mechanism which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent dysfunction during continued treatment, wild-type Gcn2 null mice were injected once daily with or phosphate buffered saline for up 14 days. Asparaginase induced mRNA expression of multiple genes greatly...
Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). We investigate hypothesis that activating transcription factor 4 (ATF4) acts as a converging point ISR during SAAR. Using liver-specific or global gene ablation strategies, both female male mice, we address role ATF4 dietary show is dispensable chronic hepatokine fibroblast growth 21 while being essential...
The athletic horse, despite being over 50% muscle mass, remains understudied with regard to the effects of exercise and training on skeletal metabolism. To begin address this knowledge gap, we employed an untargeted metabolomics approach characterize exercise-induced fitness-related changes in eight unconditioned Standardbred horses (four male, four female) before after a 12-week period. Before training, showed high degree individual variation metabolome, resulting very few differences...
The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). study objective was to investigate protective role activating transcription factor 4 (ATF4) in controlling hepatic transcriptome mediating GCN2-mTORC1 during asparaginase. We compared global gene expression patterns livers from wildtype, Gcn2 -/-, Atf4 -/- mice treated with or excipient further explored selected...
Phytoecdysteroids such as 20-hydroxyecdysone (20HE) are nutritional supplements marketed enhancers of lean body mass. In this study the impact 20HE ingestion on protein kinase B/Akt-mechanistic target rapamycin complex 1 signaling in skeletal muscle and liver male rats was found to be limited. Bioavailability 20HE, whether consumed alone or with leucine, also remained low at all doses ingested. Additional work is necessary clarify mechanism action vivo.
Abstract Dietary removal of an essential amino acid (EAA) triggers the integrated stress response (ISR) in liver. Herein, we explored mechanisms that activate ISR and execute changes transcription translation according to missing EAA. Wild‐type mice lacking general control nonderepressible 2 ( Gcn2 ) were fed complete diet or a devoid either leucine sulfur acids (methionine cysteine). Serum liver concentrations significantly reduced within first 6 h feeding leucine, corresponding with...
Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but pathophysiology remains obscure. In liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined consequences treatment on pancreata wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated 8 days were increased (P < 0.05) above all other...
The circadian clock and aging are intertwined. Disruption to the normal diurnal rhythm accelerates corresponds with telomere shortening. Telomere attrition also correlates increase cellular senescence incidence of chronic disease. In this report, we examined association White Collar 2 (WC-2) in Neurospora BMAL1 zebrafish mice found that these transcription factors associate DNA a rhythmic fashion. We identified Telomeric Repeat-containing RNA (TERRA), lncRNA transcribed from telomere. TERRA...
This paper details the discovery that GCN2 activation is required in both male and female mice to maintain core body temperature during acute cold exposure. The results point a novel role for supporting adaptive thermogenesis via amino acid transport actomyosin mechanics brown adipose tissue.
Abstract The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this relies in part on BT2, small molecule that promotes BCAA oxidation is protective mouse models these pathologies. BT2 other analogs allosterically inhibit ketoacid dehydrogenase kinase (BCKDK) promote oxidation, which presumed underlie the salutary effects...
Abstract Dietary sulfur amino acid restriction (SAAR) protects against diet-induced obesity, extends healthspan, and coincides with an overall reduction in hepatic protein synthesis. To explore the underpinnings of SAAR-induced slowed growth its impact on liver metabolism proteostasis, we resolved changes mRNA abundances compared synthesis rates individual proteins. achieve this, adult male mice were provided deuterium-labeled drinking water while freely consuming either a regular-fat or...
Asparaginase is an amino acid-depleting agent used to treat blood cancers. Metabolic complications due asparaginase affect liver function in humans. To examine how the response changes during maturity adulthood, here we treated juvenile (2-week), young adult (8-week), and mature (16-week) mice with drug or excipient for 1 week conducted RNA-Seq functional analyses. reduced body growth mass juveniles but not animals. Unbiased exploration of effect on transcriptome revealed that integrated...
Abstract A stress adaptation pathway termed the integrated response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that eIF2 kinase GCN2 is required for sustained growth androgen-sensitive and castration-resistant models of PCa both vitro vivo, patient samples. Using RNA-seq transcriptome analysis a CRISPR-based phenotypic screen, was shown regulate expression over 60 solute-carrier ( SLC ) genes, those involved amino acid transport loss...
Disruptions in biological rhythms are associated with the development of metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor amino acid insuffciency and activator integrated stress response (ISR), plays an integral role liver metabolism. The objective this work was to examine impact feeding low protein quality (LPQ) diet on diurnal We hypothesized that activation ISR by GCN2 maintains within during LPQ feeding. To address our objective, wild type (WT) whole body...
Disruptions in circadian rhythms are associated with an increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor amino acid insufficiency and activator the integrated stress response (ISR), has emerged as conserved regulator clock multiple organisms. The objective this study was to examine diurnal patterns hepatic ISR activation liver whole body metabolism. We hypothesized that GCN2 cues signaling over natural 24-h feeding-fasting cycle. To...