Mediators of chronicity in autoimmune endocrinopathies.

PROJECT SUMMARY / ABSTRACT (PRINCIPAL PROJECT) PRINCIPAL PROJECT: Molecular and cellular mechanisms of chronicity in autoimmune endocrinopathies Autoimmune endocrinopathies are chronic diseases, in which patients suffer permanent tissue damage and require lifelong hormone replacement. In Type 1 Diabetes (T1D), for example, autoimmune destruction of insulin-

producing beta cells does not remit, and patients require long-term exogenous insulin administration. Exogenous insulin regimens do not entirely mimic the exquisite control of physiologic hormone secretion, however, and often leaves patients with sub-optimal glucose control. Unlike most other autoimmune conditions, autoimmune

endocrinopathies are not currently treated with immunotherapies first-line, despite overwhelming evidence for their autoimmune cause. Here, we will test the hypothesis that chronicity in human autoimmune endocrinopathies is driven by epigenetic and molecular mechanisms that promote progenitor self-renewal and conversion to

pathogenic effectors. In Aim 1, we will determine the role of the epigenetic regulator UTX in promoting progenitor to effector conversion. Our preliminary data in mouse models identified a role for UTX in mouse CD8+ T cell progenitor to effector conversion, and we will determine whether parallel pathways exist to regulate human CD8+

T cell progenitor to effector conversion. In Aim 2, we will identify epigenetic and molecular factors important in stem-like progenitor self-renewal. Identifying immune mechanisms that underlie chronicity in autoimmune endocrinopathies will lead to new therapeutic approaches for terminating the long-term autoimmune response.

In both Aims, we will test the effects of small molecule inhibitors and biologic antagonists that target pathways important in autoimmune chronicity in order to enhance the translational potential of our studies to the clinical realm.