Project Abstracts - CTAR

Seung Kim, MD, PhD, Investigator, Stanford University
Andrew Stewart, MD, Investigator, Ichahn School of Medicine at Mount Sinai
Marcela Brissova, MD, co-Investigator, Vanderbilt University
Rita Bottino, PhD, co-Investigator, Children’s Hospital of Pittsburgh
Chunhua Dai, MD, co-Investigator, Vanderbilt University
Peng Wang, PhD, co-Investigator, Ichahn School of Medicine at Mount Sinai

Start Date: September 30, 2014
End Date: June 30, 2019

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Abstract

Our group of investigators seeks to understand and define the molecular signatures and proliferative properties of “juvenile” (< 10 years of age) human β cells in order to develop strategies to promote adult human β cell function, proliferation, and regeneration. While there have been remarkable advances in our understanding of the proliferative properties of rodent β cells, we are unable to safely stimulate the proliferation human β cells. Partly this is due to differences in human and rodent β cells, but a major limitation has been the lack of physiologically appropriate and safe examples of human β cell proliferation. Fortunately, we believe the challenges and limitations related to human β cell proliferation can now be addressed due both to discoveries by our research team members and the availability of juvenile human pancreatic specimens and islets in which there is physiologically appropriate expansion of human β cell mass. This proposal is based on recent observations that within the first decade after birth, robust human β cell proliferation leads a marked expansion of human β cell mass. Discoveries by our team have shown that juvenile human islets have distinctive differences from adult human islets and respond to proliferative stimuli such as platelet-derived growth factor (PDGF) and glucagon-like peptide-1 (GLP-1). Prolactin and human placental lactogen do not stimulate human β cell proliferation, but a recent finding from our group suggests how to overcome this limitation. We hypothesize that juvenile β cells have active signaling pathways in response to mitogenic stimuli such as PDGF, GLP-1, and prolactin, but that these become inactive in adult human β cell. We postulate that understanding these age-related changes will provide pathways to simulate growth of adult human β cells. Our broad-based, complimentary and interdisciplinary scientific team with expertise in human pancreatic islet biology, cell proliferation, and human islet cell sorting is pursing three aims: 1) Investigate in vivo proliferation of juvenile human β cells in response to PDGF, GLP-1, and Prolactin. 2) Reconstitute in vitro and in vivo responsiveness of adult human β cells to PDGF and Prolactin. 3) Decode the signaling basis for age-dependent human β cell proliferation. In addition, our team will bring to HIRN substantial experience with acquiring and studying human juvenile pancreas and islets and a set of unique human pancreatic tissues that will enable studies not previously possible.

Publications

• Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners
• AnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics
• Genetic risk converges on regulatory networks mediating early type 2 diabetes
• Human Pseudoislet System for Synchronous Assessment of Fluorescent Biosensor Dynamics and Hormone Secretory Profiles
• Exocrine pancreas in type 1 and type 2 diabetes: different patterns of fibrosis, metaplasia, angiopathy, and adiposity
• Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2
• Peeling the onion: another layer in the regulation of insulin secretion
• Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss
• CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction
• RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes
• Microvessels enhance vascularization and function of transplanted insulin-producing cells
• Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes
• Human islet T cells are highly reactive to preproinsulin in type 1 diabetes
• Combinatorial transcription factor profiles predict mature and functional human islet α and β cells
• What is a β cell? – Chapter I in the Human Islet Research Network (HIRN) Review Series
• Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass
• The Human Islet: Mini-organ with Mega-impact
• Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration
• Type 1 diabetes mellitus: much progress, many opportunities
• Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets
• Nrf2: The Master and Captain of Beta Cell Fate
• RIPK3-mediated inflammation is a conserved β cell response to ER stress
• SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells
• A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes
• Pancreatlas: Applying an Adaptable Framework to Map the Human Pancreas in Health and Disease
• Dapagliflozin does not directly affect human α or β cells
• Decreased pancreatic acinar cell number in type 1 diabetes
• Integrated human pseudoislet system and microfluidic platform demonstrates differences in G-protein-coupled-receptor signaling in islet cells
• Lactation improves pancreatic β cell mass and function through serotonin production
• Structure-Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation
• Pancreatic Islet Beta Cell-Specific Deletion of G6pc2 Reduces Fasting Blood Glucose
• GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration
• Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor
• Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable
• Lipid Droplet Accumulation in Human Pancreatic Islets is Dependent Upon Both Donor Age and Health
• Pharmacologic and genetic approaches define human pancreatic beta cell mitogenic targets of DYRK1A inhibitors
• Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation
• Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice
• Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A
• Myc Is Required for Adaptive ß-Cell Replication in Young Mice but Is not Sufficient in One-Year-Old Mice Fed with a High-Fat Diet
• Imaging mass spectrometry enables molecular profiling of mouse and human pancreatic tissue
• HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of islet β-Cells from Donors with Type 1 Diabetes
• Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions
• Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells
• Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks
• Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally
• Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis
• Discovering human diabetes-risk gene function with genetics and physiological assays
• CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition
• β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes
• Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity
• A Chromatin Basis for Cell Lineage and Disease Risk in the Human Pancreas
• Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation
• Advances in drug discovery for human beta cell regeneration
• Cystic fibrosis-related diabetes is caused by islet loss and inflammation
• Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4(+) T Cells in Patients With Type 1 Diabetes
• α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes
• CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets
• Suppression of Insulin Production and Secretion by a Decretin Hormone
• Replication confers β cell immaturity
• Identification of Newly Committed Pancreatic Cells in the Adult Mouse Pancreas
• Transcriptional Noise and Somatic Mutations in the Aging Pancreas
• Loss of mTORC1 Signaling Alters Pancreatic α Cell Mass and Impairs Glucagon Secretion
• Insights into Beta Cell Regeneration for Diabetes via Integration of Molecular Landscapes in Human Insulinomas
• Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns
• β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells
• Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling
• Signals in the pancreatic islet microenvironment influence β-cell proliferation
• Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors
• Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation
• Age-Dependent Decline in the Coordinated [Ca(2+)] and Insulin Secretory Dynamics in Human Pancreatic Islets
• Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx
• Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary?
• Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes
• G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance
• Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration
• G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress
• Replicative capacity of β-cells and type 1 diabetes
• Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function
• Stress-impaired transcription factor expression and insulin secretion in transplanted human islets
• p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion
• Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion
• Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells
• Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish
• Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells
• The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice
• Current concepts on the pathogenesis of type 1 diabetes–considerations for attempts to prevent and reverse the disease
• Human β-cell proliferation and intracellular signaling: part 3
• Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles
• Suppression of insulin production and secretion by a decretin hormone