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Principal Investigator: Han Zhu
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $158,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing β-cells in the pancreatic
islets. Several theories have been proposed to explain T1D pathogenesis including aberrant immune cell activity
as well as increased β-cell sensitivity to inflammatory and metabolic stressors. It has become increasingly
apparent that β-cells may not be passive immune cell targets but can contribute to the disease intrinsically.
However, it remains unclear whether the risk of developing T1D is already introduced during β-cell formation.
Postnatal β-cell maturation may be a T1D relevant β-cell developmental process, not only because it occurs
during the peak incidence of T1D diagnosis but also because it determines whether an individual has an
adequate functional β-cell pool to cope with environmental stressors. However, the mechanisms underlying
human β-cell maturation have been understudied due to the absence of an appropriate human β-cell model.
While human pluripotent stem cell (hPSC)-derived β-cells (SC-β-cells) hold immense potential for modeling T1D,
current production methods do not permit proper functional maturation, hampering their utility in studying β-cell
maturation. One of the hallmark features of mature β-cells is glucose-induced mitochondrial respiration, which is
lacking in SC-β-cells. It has been suggested that environmental cues, such as nutrients and circadian rhythm,
drive β-cell maturation and establish a mature β-cell state through gene expression regulation and epigenetic
modifications. Our objective is to uncover gene regulatory mechanisms that underlie the acquisition of glucose-
dependent mitochondrial function in human β-cells and assess the suitability of SC-β-cells as a model for
studying β-cell maturation. This work will leverage the genomic and genetic methodologies that we have
previously developed for SC-β-cells, including a platform for genome-wide functional perturbation screening,
single-cell genomics assays, and a computational tool to infer gene regulatory networks. Expanding on our
preliminary studies, we propose to investigate and modify key transcriptional programs governing SC-β-cell
mitochondrial activity and induce maturation in vitro (Aim 1). Mechanistically, we plan to investigate the
correlation between changes in SC-β-cell function and the epigenome that occurs during the maturation process
(Aim 2). It has been established that SC-β-cells exhibit improved function following engraftment into mice. Thus,
in the second aim of our study, we will also investigate epigenetic alterations that occur during this in vivo
maturation process. We anticipate that our in vitro manipulation of key transcriptional programs will induce similar
epigenetic remodeling as observed in vivo. Together, our proposed study will advance the culture of SC-β-cells
and demonstrate their utility as a model for investigating human β-cell maturation.
Terms: <Acceleration><Assay><Autoimmune Status><Autoimmunity><B9 endocrine pancreas><Beta Cell><Bioassay><Biological Assay><Birth><Brittle Diabetes Mellitus><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Death><Cell Function><Cell Maturation><Cell Physiology><Cell Process><Cell Respiration><Cell model><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Respiration><Cellular model><Chronic><Circadian Rhythms><Computational toolkit><Cues><D-Glucose><Development><Developmental Process><Dextrose><Diagnosis><Disease><Disorder><Endocrine Pancreas><Engineering><Engraftment><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exhibits><Exposure to><F-SRC-1><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Generations><Genes><Genetic><Genetic Risk><Genetic Transcription><Genomics><Glucose><Goals><Histone Acetylase><Human><Humulin R><IDDM><Immune><Immune system><Immunes><In Vitro><Incidence><Individual><Inflammation><Inflammatory><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Islands of Langerhans><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Link><Maps><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Methodology><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Modification><Murine><Mus><NCOA1><NCOA1 gene><NCoA-1><Nature><Neonatal><Nesidioblasts><Novolin R><Nuclear Orphan Receptor><Nuclear Receptors><Nutrient><Nutrient availability><Nyctohemeral Rhythm><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Pancreatic Islets><Pancreatic beta Cell><Pancreatic β-Cell><Pars endocrina pancreatis><Parturition><Pathogenesis><Patients><Play><Process><Production><Progenitor Cells><RNA Expression><Regular Insulin><Regulator Genes><Repression><Research><Research Design><Research Resources><Resources><Respiration><Risk><Risk-associated variant><Role><Stress><Structure of beta Cell of islet><Study Type><Study models><Subcellular Process><Sudden-Onset Diabetes Mellitus><T1 DM><T1 diabetes><T1D><T1DM><Testing><Thesaurismosis><Transcription><Transcriptional Regulatory Elements><Transplantation><Twenty-Four Hour Rhythm><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Work><aerobic metabolism><aerobic respiration><autoimmune attack><autoimmune destruction><autoimmune pathogenesis><cell behavior><cell replacement therapy><cell replacement treatment><cell type><cellular behavior><circadian process><computational toolbox><computational tools><computational toolset><computerized tools><coping><daily biorhythm><developmental><diabetes pathogenesis><disease model><disorder model><early childhood><environmental change><environmental stresses><environmental stressor><epigenetic regulation><epigenetically><epigenome><experiment><experimental research><experimental study><experiments><fetal><functional improvement><gene locus><gene regulatory network><genetic locus><genome scale><genome-wide><genomewide><genomic data><genomic data-set><genomic dataset><genomic location><genomic locus><global gene expression><global transcription profile><histone acetyltransferase><histone methylation><histone modification><human pluripotent stem cell><improve function><improved><improved functional outcomes><in vivo><insulin dependent diabetes><insulin dependent type 1><insulin secretion><islet><islet progenitor><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><metabolism disorder><mitochondrial><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oxidative metabolism><pancreas beta cell><pancreas β cell><pancreatic b-cell><postnatal><programs><regulatory gene><respiratory mechanism><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><single cell genomics><social role><stem cells><stressor><study design><theories><trans acting element><transcriptome><transplant><type I diabetes><type one diabetes><β-cell><β-cells><βCell>