A5020908845- Pancreatic function and diabetes
- Diabetes and associated disorders
- Cholesterol and Lipid Metabolism
- Diet, Metabolism, and Disease
- FOXO transcription factor regulation
- Metabolism, Diabetes, and Cancer
- Lipid metabolism and biosynthesis
- Genomics, phytochemicals, and oxidative stress
- Adipose Tissue and Metabolism
- Diabetes Management and Research
- Genetics and Neurodevelopmental Disorders
- Glycosylation and Glycoproteins Research
- Pregnancy and preeclampsia studies
- Peroxisome Proliferator-Activated Receptors
- 14-3-3 protein interactions
- Neonatal Health and Biochemistry
- Adipokines, Inflammation, and Metabolic Diseases
- Thyroid Disorders and Treatments
- Blood Coagulation and Thrombosis Mechanisms
- Epigenetics and DNA Methylation
- Diabetes Treatment and Management
- RNA modifications and cancer
- Birth, Development, and Health
- RNA Research and Splicing
- Steroid Chemistry and Biochemistry
Icahn School of Medicine at Mount Sinai
2015-2025
Child Health and Development Institute
2020-2025
New York Proton Center
2018-2019
National Institute of Diabetes and Digestive and Kidney Diseases
2013-2015
National Institutes of Health
2013-2015
University of Geneva
2009-2012
University Hospital of Geneva
2009-2010
The Pax6 transcription factor is crucial for endocrine cell differentiation and function. Indeed, mutations of are associated with a diabetic phenotype drastic decrease insulin-positive number. Our aim was to better define the β-cell transcriptional network thus provide further information concerning role in We developed Pax6-deficient model rat primary β-cells specific small interfering RNA leading 75% knockdown expression. Through candidate gene approach, we confirmed that controls mRNA...
Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or loss. This bi-directional effect of stress is not understood at the functional level. Here we tested hypothesis that pre-stress level adaptive thermogenesis brown adipose tissue (BAT) functions explain vulnerability resilience stress-induced obesity.
The paired box homeodomain Pax6 is crucial for endocrine cell development and function plays an essential role in glucose homeostasis. Indeed, mutations of are associated with diabetic phenotype. Importantly, homozygous mutant mice characterized by markedly decreased β δ cells absent α cells. To better understand the critical that exerts glucagon-producing cells, we developed a model primary rat study transcriptional network adult differentiated generated Pax6-deficient using either specific...
Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here, we generated β-cell–specific conditional knockout gain-of-function mouse models used human islet transplant experiments to examine how manipulating Nrf2 levels affects survival, proliferation, mass. Depletion in β-cells results decreased glucose-stimulated proliferation ex vivo adaptive expansion after high-fat diet vivo. protects from apoptosis diet. loss function decreases Pdx1...
The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation death. 14-3-3 binding ChREBPα results in cytoplasmic retention suppression of transcriptional activity. Thus, small molecule-mediated stabilization this protein-protein interaction (PPI) may be...
Carbohydrate-responsive element–binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has low glucose inhibitory domain (LID) that restrains the transactivation when catabolism minimal. A novel ChREBP (ChREBPβ) was recently described lacks LID therefore constitutively more potently active. ChREBPβ not been nor its role determined. We found highly expressed...
Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose, a natural mitogen, drives adaptive expansion mass by promoting proliferation. We previously demonstrated carbohydrate response element-binding protein (ChREBPα) is required for glucose-stimulated proliferation and overexpression ChREBPα amplifies the proliferative effect glucose. Here we found reprogrammed anabolic metabolism to promote increased mitochondrial biogenesis, oxygen...
Overnutrition can alter gene expression patterns through epigenetic mechanisms that may persist generations. However, it is less clear if overnutrition, for example a high fat diet, modifies control of in adults, or by what molecular mechanisms, such contribute to the pathology metabolic syndrome. Here we test hypothesis diet alters hepatic DNA methylation, transcription and patterns, explore contribution changes pathophysiology obesity.RNA-seq targeted high-throughput bisulfite sequencing...
Failure to expand pancreatic β-cells in response metabolic stress leads excessive workload resulting β-cell dysfunction, dedifferentiation, death, and development of type 2 diabetes. In this study, we demonstrate that induction Myc is required for increased replication expansion during stress-induced insulin resistance with short-term high-fat diet (HFD) young mice. β-Cell-specific knockout mice fail adaptively show impaired glucose tolerance dysfunction. Mechanistically, PKCζ, ERK1/2, mTOR,...
Abstract Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform carbohydrate response-element binding protein (ChREBPβ) nuclear effector hyperglycemic stress occurring in β-cells response to prolonged glucose exposure, high-fat diet, We transient positive feedback induction ChREBPβ necessary adaptive metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression results loss identity, apoptosis, mass,...
In this article, we describe novel conditions for culture, expansion, and transdifferentiation of primary human dermal fibroblasts (hDFs) to induce expression transcription factors (TFs) hormones characteristic the islets Langerhans. We show that histones associated with insulin gene are hyperacetylated DNA is less methylated in islet cells compared do not express insulin. Using two compounds alter epigenetic signature cells, romidepsin (Romi), a histone deacetylase inhibitor, 5-Azacytidine...
Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) enzyme required maintain zebrafish embryos both primary malignant mammalian cells. The functional consequences MPI loss striking:...
Since individual cells from freshly isolated white adipose tissue (WAT) exhibit variable levels of fat accumulation, we attempted to determine which factor(s) cause this variation. We used primary WAT adult mice and the mouse 3T3-L1 cell-line preadipocytes for these studies. Cells were labeled with BODIPY (boron-dipyrromethene) lipid probe, a marker accumulation in live cells, sorted on fluorescence-activated cell sorter into two populations exhibiting low or high fluorescence intensity....
Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), a mediator of inflammation upregulated in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation survival isolated mouse human islets ex vivo. Here, we analyzed whether systemic could enhance mass identity the setting type using mice with spontaneous mutation leptin (Leprdb). Four- or six-week-old, db/+,...
Increasing brown adipose tissue (BAT) activity is regarded as a potential treatment of obese, hyperglycemic patients with metabolic syndrome. Triiodothyronine (T3) known to stimulate BAT by increasing mitochondrial uncoupling protein 1 (Ucp1) gene transcription, leading increased thermogenesis and decreased body weight. Here we report our studies on the effects T3 glucose in two mouse models immortalized preadipocytes culture. We identified carbohydrate response element binding (ChREBP)...
Pax6 is important in the development of pancreas and was previously shown to regulate pancreatic endocrine differentiation, as well insulin, glucagon, somatostatin genes. Prohormone convertase 2 (PC2) main processing enzyme alpha cells, where it processes proglucagon produce glucagon under spatial temporal control 7B2, which functions a molecular chaperone. To investigate role biosynthesis, we studied potential target genes InR1G9 cells transfected with small interfering RNA clones...
The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. aim this study was determine the role EGFR ligand heparin-binding EGF-like (HB-EGF) proliferative response glucose, a mitogen and key regulator mass increased insulin demand. show exposure isolated rat human islets HB-EGF stimulates proliferation. In islets, inhibition...
Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation function. In the present study, we asked whether T3 signaling pathways coordinately regulate transcription genes important for function proliferation.
The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation death. 14-3-3 binding ChREBPα results in cytoplasmic retention suppression of transcriptional activity. Thus, small molecule-mediated stabilization this protein-protein interaction (PPI) may be...
Proteinase-activated receptor-1 (PAR-1) and PAR-2 have been associated with increased invasiveness metastasis in human malignancies. The role of PAR-3 has less investigated. We examined the PARs a pancreatic adenocarcinoma PANC-1 cell line phenotype vitro.We knocked down PAR-1, PAR-2, or PAR-3, whereas empty vector-infected cells served as controls. Specific peptide agonists were used to stimulate receptors. In vitro assays colony formation, migration, invasion characterize phenotypes,...
We showed previously that proliferating human islet-derived de-differentiated cells (DIDs) exhibit many characteristics of mesenchymal stem cells. Dispersed DIDs can be induced by serum deprivation to undergo mesenchymal-to-epithelial transition and aggregate into epithelial cell clusters (ECCs). Conversely, ECCs disperse epithelial-to-mesenchymal (EMT) re-addition mammalian sera. In this study, we show platelet-derived growth factor BB (PDGF-BB) mimics mediates serum-induced ECCs' dispersal...