Tuesday, May 21, 2024
5/21/2024
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.
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