Project Abstracts - CBDS

Al Powers, PhD, Investigator, Vanderbilt University
Richard Caprioli, PhD, Investigator, Vanderbilt University
Jeremy Norris, PhD, co-Investigator, Vanderbilt University
Long Cai, PhD, Investigator, California Institute of Technology
Viviana Gradinaru, PhD, Investigator, California Institute of Technology
Marcela Brissova, PhD, co-Investigator, Vanderbilt University

Start Date: September 25, 2015

End Date: May 31, 2020 *

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Abstract

This team brings expertise in pancreas development and physiology, mechanistic studies of the disturbance of pancreas function in diabetes, and also in the development, application and continued optimization of novel methods for high-resolution tissue imaging and single-cell analysis. We will define the normal and dynamic alterations in tissue architecture, cellular-level molecular signatures, and physiological functions, of the human pancreatic islet that occur specifically between 0-5 years of age (the “juvenile period”), which is now emerging as a critical period of development and maturation for this essential organ. While our understanding over this period is limited, new data suggest that the pancreas exhibits a surprising degree of plasticity and maturation in its global tissue architecture, beta-cell physiological function, and the latter’s interplay not only with other hormone-secreting cell types but also the vascular and neural networks. Because very early onset autoimmunity – as measured by antibodies against functional proteins of the human β cell – has been detected within this same juvenile period, it is possible that “cryptic” pancreas/islet defects arising within the juvenile period are a strong driver of future type 1 diabetes (T1D). We hypothesize that these defects within the juvenile period arise because abnormalities in the normal dynamic maturation of islet structure and physiology either improperly engage an imperfectly functioning immune system, or improperly present antigens to a relatively normal immune system, both leading to inadequate tolerance. Many critical aspects of juvenile β-cell development and function (for example, transition from amino-acid- to glucose-responsiveness) are still not known, rooted in a problem of tissue scarcity and because tissues were not prepared in a way conducive for modern analytical approaches. We use advanced tissue-clearing technologies, multiplexed RNA in situ tissue-analysis approaches, and imaging mass spectrometry, and have substantial experience in studying the differentiation and function of human juvenile pancreas. We will be able to apply these novel methods efficiently because we have gained control over the pipeline for tissue procurement and preparation. We will overcome the paucity of information in human tissue about the many developmental regulators that are well known from studies in rodents. Our analyses will provide essential fundamental underpinnings for a structure-function atlas of the human pancreas, especially over the juvenile period, and at the tissue architecture and single-cell level will likely uncover significant findings regarding cellular heterogeneity. We will study key cell-surface, physiological markers, transcription factors, and other markers to define the sequence of events in human juvenile islet development. We also focus on the intra- and inter-islet vascular and neural networks, and the putative role of tissue macrophages. These methods of comprehensive profiling will be applicable to T1D pancreas samples.

Publications

• 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
• 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
• AnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics
• 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
• 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
• Type 1 diabetes mellitus: much progress, many opportunities
• 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
• 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
• 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
• 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
• 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
• Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis
• β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes
• Cystic fibrosis-related diabetes is caused by islet loss and inflammation
• α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes
• Age-Dependent Decline in the Coordinated [Ca(2+)] and Insulin Secretory Dynamics in Human Pancreatic Islets
• 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
• Replicative capacity of β-cells and type 1 diabetes
• Stress-impaired transcription factor expression and insulin secretion in transplanted human islets