This initiative will support the development of tools and experimental platforms for the purification and characterization of Extracellular Vesicles (EV) originating from the human pancreatic islet and its broader tissue environment in healthy individuals, and individuals with T1D or at-risk of developing the disease. It will also support the exploration of the contribution of pancreatic EV biology to islet function, dysfunction and T1D disease initiation; the development of EV-based diagnostic tools for disease monitoring and classification; and the use of pancreatic EV biology to identify novel therapeutic targets.
Type 1 Diabetes (T1D) is a progressive immune-mediated disease that is preceded by an asymptomatic period of highly variable duration in humans. It is believed that this asymptomatic phase of the disease process involves the activation of beta cell injury, stress or senescence pathways, leading to the development of an autoimmune response specifically targeted to beta cells. Other cell types within the larger pancreatic tissue environment, to include endocrine, exocrine, vascular or perivascular cells and various kinds of resident or trafficking immune cells, may also contribute to the development of an inflammatory milieu and/or the initiation of T1D in humans. While the appearance of early onset T1D can be predicted in at-risk individuals through the detection of multiple autoantibodies in the peripheral blood, there are currently no molecular biomarkers to help diagnose and monitor disorders associated with beta cell dysfunction or islet inflammation during the asymptomatic phase, nor is there a targeted molecular therapy for the timely prevention of beta cell injury or restoration of pancreatic tissue integrity in at risk individuals before autoimmunity develops.
Emerging data suggest that Extracellular Vesicles (EVs) that are produced by pancreatic beta cells or by nearby cells within the peri-islet environment, including exosomes, apoptotic bodies and microvesicles, may act as paracrine effectors in islet health and may represent the missing link between inflammation and autoimmunity in early T1D. For example, recent findings suggest that EVs could play a role in autoreactive recognition and antigen presentation at the beta/immune cell interface, thereby contributing to triggering or maintaining pathological autoimmune responses in T1D. As demonstrated in a wide variety of organ systems and disease situations, tissue- or cell-specific EVs can serve as highly informative biomarkers of normal and pathophysiological states, and can be detected in culture supernatants and biological fluids including plasma, urine, saliva, synovial fluid, cerebrospinal fluid and tears. A greater understanding of the biology behind human pancreas-associated EV populations could shed light on their contribution to islet function and dysfunction, and on their role in T1D pathogenesis. Analysis of the molecular cargos found in various human pancreas-derived EV populations, and of the regulatory pathways impacted by specific EV cargo molecules, could lead to the development of diagnostic tools to monitor islet health and disease progression, or the identification of novel molecular targets for therapeutic applications.
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