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Principal Investigator: MANAMI HARA
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $764,894
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Increasing evidence has demonstrated that disease states of either endocrine or exocrine pancreas aggravate
one another, which implies bi-directional blood flow between islets and exocrine cells. However, this is
inconsistent with the current model of uni-directional blood flow, which is strictly from islets to exocrine tissues,
termed insulo-acinar portal system. Furthermore, exocrine and endocrine compartments of the pancreas have
been studied by different scientific communities, and the diseases of them are treated by physicians in different
medical disciplines, gastroenterologists and endocrinologists, respectively. Notably, it is still unknown why
pancreatic islets, consisting only 1-2% of the pancreas, are embedded in the bulk exocrine tissue as one organ.
We have previously shown that islet microcirculation is integrated with that of surrounding exocrine tissue at its
entirety through intravital in vivo recordings of fluorescent-labeled red blood cell flow as well as in situ imaging
of pancreas vasculature using thick tissue blocks. This new model of the bi-directional blood flow physically links
both compartments. Further anatomical analysis of the spatial relationship between islets and blood vessels has
revealed that the majority of islets had no association with arterioles. Islets with a direct contact with an arteriole
are significantly larger, a pattern that has been observed throughout the examined mammalian species: human,
monkey, pig, rabbit, ferret, and mouse. We hypothesize that the arterioles emerge to feed the bulk exocrine
pancreas regionally with no preferential targeting of individual islets. Vascularizing the pancreas in this way may
allow an entire downstream region of islets and acinar cells to be simultaneously exposed to changes in the
blood levels of nutrients, hormones digestive enzymes and other circulating factors, which could underlie the
pathogenesis of pancreatic diseases including diabetes. In this application, this hypothesis will be tested by
modeling the pancreas blood flow crosstalk using in vivo models (Aim 1). In parallel, the characteristics of the
human pancreatic vascular network will be examined using our unique collection of the whole human pancreata
(currently n>210 spanning the lifetime from 7-days to 85 years of age) and specimens from the Network for
Pancreatic Organ Donors with Diabetes (nPOD) (Aim 2). In this multi-disciplinary proposal, we have assembled
complementary expertise that widely cover all necessarily research fields to accomplish the propose projects:
endocrine and exocrine microcirculation, advanced animal surgery, vascular biology, endocrinology, diabetes,
beta-cell/islet physiology and biology, genetics, pathology, gastroenterology, pancreatitis and pancreatic cancer,
allogeneic and autologous islet transplantation, and immunology.
Terms: <3-D><3-D Imaging><3-D analysis><3-Dimensional><3-dimensional analysis><3D><3D analysis><3D imaging><Acinar Cell><Aciner Cells><Acute><Adult-Onset Diabetes Mellitus><Age Years><Allogenic><Anatomic Sites><Anatomic structures><Anatomy><Animals><Autoimmune Diseases><B9 endocrine pancreas><Beta Cell><Biology><Blood Glucose><Blood Sugar><Blood Vessels><Blood capillaries><Blood erythrocyte><Blood flow><Body Tissues><Brittle Diabetes Mellitus><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Morphology><Cellular Physiology><Cellular Process><Characteristics><Childhood><Chronic><Clinical><Collection><Communities><Complex><Data><Dedications><Defect><Detection><Deterioration><Developmental Process><Diabetes Mellitus><Diffusion><Discipline><Disease><Disorder><Domestic Rabbit><Educational process of instructing><Endocrine><Endocrine Gland Secretion><Endocrine Pancreas><Endocrinologist><Endocrinology><Endothelial Cells><Enzyme Gene><Enzymes><Erythrocytes><Erythrocytic><Exocrine pancreas><Exposure to><Failure><Family suidae><Ferrets><Food><Gastroenterologist><Gastroenterology><Genetic><Hormones><Human><Human Characteristics><Human Nature><Humulin R><IDDM><Immunology><Impairment><In Situ><In vivo analysis><Inbred NOD Mice><Individual><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Islands of Langerhans><Islands of Langerhans Transplantation><Islands of Pancreas Transplantation><Islet Cell><Islets of Langerhans><Islets of Langerhans Grafting><Islets of Langerhans Transplantation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Label><Link><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Maps><Marrow erythrocyte><Maturity-Onset Diabetes Mellitus><Measurement><Measures><Medical><Metabolism and Endocrinology><Mice><Mice Mammals><Microcirculation><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Monitor><Monkeys><Murine><Mus><NIDDM><NOD Mouse><Nesidioblasts><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Obese Diabetic Mice><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonobese Diabetic Mouse><Novolin R><Onset of illness><Operative Procedures><Operative Surgical Procedures><Organ><Organ Donor><Oryctolagus cuniculus><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Pancreatic Diseases><Pancreatic Disorder><Pancreatic Islets><Pancreatic Islets Transplantation><Pancreatitis><Pars endocrina pancreatis><Pathogenesis><Pathology><Patients><Pattern><Physicians><Physiology><Pigs><Population><Portal System><Rabbits><Rabbits Mammals><Red Blood Cells><Red Cell><Regular Insulin><Reporting><Research><Research Specimen><Slow-Onset Diabetes Mellitus><Specimen><Stable Diabetes Mellitus><Structure><Subcellular Process><Sudden-Onset Diabetes Mellitus><Suidae><Surgical><Surgical Interventions><Surgical Procedure><Swine><Symptoms><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Teaching><Technology><Testing><Therapeutic Hormone><Thick><Thickness><Three-Dimensional Imaging><Three-dimensional analysis><Tissues><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Vascular blood supply><Vascularization><Visit><adult onset diabetes><age associated><age correlated><age dependent><age linked><age related><age specific><arteriole><autoimmune condition><autoimmune disorder><autoimmunity disease><autologous islet transplantation><blood corpuscles><blood supply><capillary><cell morphology><density><diabetes><diabetic><diffused><diffuses><diffusing><diffusions><disease onset><disorder onset><exocrine pancreatic><in situ imaging><in vivo><in vivo Model><in vivo evaluation><in vivo testing><indexing><insulin dependent diabetes><insulin dependent type 1><insulin signaling><insulitis><islet><islet auto transplantation><islet beta cell transplantation><islet cell transplant><islet cell transplantation><islet progenitor><islet transplantation><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><maturity onset diabetes><molecular profile><molecular signature><mouse model><multidisciplinary><murine model><non-obese diabetic (NOD) mice><nonobese diabetic (NOD) mice><nutrient blood level><pancreas disorder><pancreas imaging><pancreatic malignancy><pediatric><porcine><spatial relationship><suid><surgery><three dimensional><transcriptomics><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><vascular><vascular supply><venule><β-cell><β-cells><βCell>