PROJECT SUMMARY Type 1 Diabetes (T1D) is an autoimmune disease affecting over 1.6 million people in the United States, and more than 5 million Americans are expected to be diagnosed with T1D by 2050. Clinical T1D is preceded by an occult period of autoimmune beta cell loss and dysfunction. Disease prediction can be performed for clinical trial purposes, with a combination of islet autoantibodies, genetic markers, and metabolic markers. However, the predictive ability in the short term, particularly early in the disease or as an early marker of response to therapy, is often inadequate. This results in needing longer and more extensive clinical trials for T1D interventions. Islet- derived exosomes (or small extracellular vesicles produced by pancreatic beta cells or nearby cells within the peri-islet environment) may reveal beta cell dysfunction and islet inflammation and are believed as promising biomarkers for early detection and monitoring of T1D, but little has been explored yet. Thus, there is an urgent and unmet need to identify and characterize islet-derived exosomes for the early detection of T1D, particularly during the asymptomatic phase. Our overall objective is to create an integrated exosome isolation and analysis system for the high throughput screening and identification of islet-derived exosomal markers with the rapid purification and specific detection of islet-derived exosomes in T1D. The rationale for the proposed work is to screen for pancreatic islet-specific exosomal markers and further develop an Exosome Technology with Optoelectronics Lab-on-chip (EXTOL) system for rapid and specific capturing and analyzing islet-derived exosomes in T1D. Then, we will validate the EXTOL system and screened exosomal markers using clinical samples from T1D patients and appropriate controls. The ultimate product of this study is to provide a new platform to screen, identify, and analyze exosomal markers for rapid and specific detection of asymptomatic T1D.