Investigating the regulation of T cell-mediated autoimmunity in type 1 diabetes by microRNA146a - PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is a chronic autoimmune disease that results in destruction of pancreatic islet beta cells by autoreactive T lymphocytes. T1D is the most common form of diabetes in children less than 15 years of age. Intensive insulin therapy is the current standard of treatment for T1D. Yet, insulin treatment does not address the underlying autoimmunity present in T1D. As such, there is a critical need for T1D therapies that target autoimmunity, which will prevent beta cell loss in early stages of T1D and allow for survival of remaining beta cells in later T1D stages. We have previously shown that spontaneous autoimmune diabetes is accelerated in non-obese diabetic (NOD) mice deficient in NF-kB c-Rel. Interestingly, c-Rel knockout NOD mice show significantly increased levels of microRNA146a (miR146a), which is a microRNA that is highly expressed in immune cells and is involved in post-transcriptional regulation of key NF-κB signaling proteins. Similarly, miR146a is increased in the serum of T1D patients at the time of diagnosis. Hence, we generated miR146a- knockout (miR146a-KO) NOD mice to study the role of miR146a in T1D. We discovered that deficiency of miR146a prevents spontaneous autoimmune diabetes in NOD mice. In this proposal, we will (a) investigate the role of miR146a in regulation of autoimmunity in T1D with a focus on T cells and T regulatory cells, and (b) study inhibition of miR146a as a potential therapy for T1D. We hypothesize that miR146a deficiency results in decreased T cell autoreactivity and enhanced T regulatory cell function, and as such, treatment with anti- miR146a will prevent autoimmunity in T1D and halt progression of T1D. We will use NOD wildtype mice and our novel miR146a-knockout NOD mice to investigate the role of miR146a in T1D, with a focus on T cell autoreactivity to T1D autoantigens and T cell polarization. We will also investigate the role of miR146a in T regulatory cell number and function in these mice with an emphasis on the direct regulation of NF-κB c-Rel by miR146a given the critical role of c-Rel in Treg development and function. Furthermore, we will use an anti-miR146a inhibitor to study the effect of miR146a inhibition in T cells and T regulatory cells from NOD mice, healthy human blood, and T1D patient blood. In vivo, we will study anti-miR146a treatment in both prediabetic and early diabetic NOD mice to examine the efficacy of miR146a inhibition for prevention and treatment of T1D. Altogether, this proposal uses novel miR146a-knockout NOD mice, T1D patient samples, and an anti-miR146a inhibitor to study the regulatory role of miR146a in autoimmunity in T1D and the efficacy of miR146a inhibition as a therapeutic for T1D. These studies have the potential to lead to a long-sought-after therapeutic approach to control T cell-mediated autoimmunity in type 1 diabetes.
