PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is characterized by the selective destruction of insulin producing ?-cells due to infiltrating autoaggressive T-cells and a break in immune tolerance. As a consequence, the patient is met with a severe loss of ?-cell function and mass thus requiring the need for exogenous insulin. Preventative immunomodulatory therapeutic strategies to improve disease outcome have been met with minimal success. Therefore, novel strategies to restore overall ?-cell function and health are warranted. Recent evidence suggests that ?-cells themselves facilitate their own complicit demise during the progression of T1D and thus may serve as potential therapeutic targets of intervention. Chronic exposure to pro-inflammatory mediators has been shown to induce ?-cell dysfunction; however, the mechanisms mediating this process have yet to be fully elucidated. In this application, we propose to study the impact of pro-inflammatory mediators on the ?-cell dialogue through exchange of circulating nanovesicles termed extracellular vesicles (EVs). We and others have noted significant content alterations in EV cargoes at the protein and miRNA level upon T1D pro- inflammatory cytokine induction. However, the direct physiological and mechanistic implications of altered pro- inflammatory ?-cell EV cargo to recipient ?-cells have yet to be fully elucidated. The long-term goal of the applicant is to establish an independent laboratory exploring the physiological and mechanistic role of EVs in the pathogenesis of T1D. The central hypothesis of the application is that ?-cells contribute to their own demise through diabetogenic ?-cell EV cargo exchange to induce ?-cell dysfunction and enhancement of antigen processing and presentation. To test this hypothesis, two specific aims have been proposed which are backed by extensive preliminary data. In Aim 1, we will test the hypothesis that pro-inflammatory ?-cell EVs activate the CXCL10:CXCR3 axis to induce ?-cell failure. In Aim 2, we will test the hypothesis that pro- inflammatory ?-cell EVs contribute to ?-cell immunomodulation during the pathogenesis of T1D. Both Aims will use ex vivo and in vivo mouse models of T1D and human islets and cell lines to address the hypotheses. The applicant is part of the highly collaborative Islet Regeneration Center (Center for Regenerative Medicine) at Mayo Clinic, Rochester, MN. This outstanding research environment in addition to a carefully selected mentoring committee comprised of established NIH-funded investigators will provide the applicant with the necessary tools and support to establish herself as an independent research investigator.
|Effective start/end date||8/1/21 → 7/31/22|
- National Institute of Diabetes and Digestive and Kidney Diseases: $154,569.00
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