Type 1 diabetes (T1D) is a serious autoimmune disease resulting from immune destruction of insulin-producing pancreatic ?-cells. While T1D is well-studied and indeed has been cured many times in rodent models, these findings have not always translated to the human disease. A fundamental barrier to curing human T1D is the incomplete understanding of its disease pathogenesis in the human host. We have pinpointed a role by primary cilia in the pancreas by mediating both ?-cell insulin secretion and crosstalk among different cell types, two aspects of pancreatic function that are critical to T1D disease initiation and progression. These results lead us to propose that pancreatic cilia may be a key determinant of the T1D disease course and thus represents a new therapeutic target. However, to-date there is very limited information about primary cilia expression, distribution, and morphology in the normal human endocrine and exocrine pancreas, and much less known about disease settings such as T1D. To address this knowledge gap, we will implement a novel, validated high-resolution imaging strategy, developed by the Hughes lab in collaboration with the Washington University Center for Cellular Imaging, to examine primary cilia on multiple cell populations in healthy versus T1D human pancreatic tissue. We hypothesize that applying our highly sensitive microscopy method to human pancreatic tissue specimens will allow cilia identification in both the endocrine and exocrine compartments of the pancreas, provide important insights on donor heterogeneity, and improve understanding of how pancreatic cilia are affected by the T1D disease process. We will test our hypothesis through two specific aims: 1) examine primary cilia distribution in human endocrine islets and compare differences between healthy vs. diabetic donors; 2) map the cilia distribution in exocrine compartments, which are much less studied in the T1D field. Integration of our cellular imaging expertise, human pancreas specimens, and a novel focus on primary cilia will advance understanding of pancreatic cilia function in health and disease.
We have developed high-resolution optical microscopy methods to study the primary cilium, an essential organelle that regulates diverse cellular functions. In this proposal, we will perform imaging experiments to study the changes in ciliary structure that are associated with the development of human type 1 diabetes. With these data, we can begin to understand cilia-dependent pathophysiology in the pancreas and help drive the development of pharmacologic agents targeting pancreatic cilia that may lead to a more effective treatment for human disease.
