Identification of Novel Targets in the Development of Complications of Diabetes
Gastroparesis is defined as a syndrome characterized by abnormal gastric function resulting in delayed gastric emptying in the absence of mechanical obstruction. Diabetic gastroparesis is a well-established complication of diabetes and occurs more frequently than previously assumed. Patients admitted with gastroparesis require more procedures, have a longer hospital stay and incur higher charges than the mean. Patients with diabetic gastroparesis are at a higher risk of having poor glycemic control due to a mismatch between emptying and glucose regulation. The availability of non-invasive methods to determine gastric emptying, of a rich source of animal data and the availability of full thickness gastric biopsies and blood samples make diabetic gastroparesis an ideal disease to mechanistically study complications of diabetes. The central hypothesis for this pilot and feasibility proposal is that transcriptomic data obtained from the study of diabetic gastroparesis will inform on mechanisms of all complications of diabetes including urological. We will test the central hypothesis in one specific aim. In hypothesis 1a we will use data obtained by deep sequencing of RNA to determine differences in gene transcripts, including novel transcripts and splice variants, between samples from diabetic patients with and without gastroparesis and use pathway analysis tools to link them to other molecules that while quantitatively normal are transcriptionally different. In hypothesis 1b we will determine the effect of RNA changes at a protein level. We will validate our rare variant findings using blood samples from diabetic controls and patients with diabetic gastroparesis. The specific aim is supported by preliminary data that show we can identify genes and pathways not previously thought to be associated with gastroparesis, supporting our proposed approach. Successful completion of this pilot and feasibility proposal has both basic and clinical implications. We will take advantage of our initial deep sequencing investments, the most recent advances in sequencing and the well documented and extensive GpCRC repositories to obtain data for a wide range of new hypotheses. We will identify signaling pathways and cellular components that are integral to the prevention or development of gastroparesis and also provide data on the effect of diabetes on cell types that are necessary not only for normal gastrointestinal function but also for the function of other smooth muscles including vascular and urologic cells.

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