Revealing LIM Domain Transcriptional Complexes that establish and maintain Beta Cell Mass

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Pancreatic islets of Langerhans contain insulin-secreting β-cells required for maintaining glucose homeostasis. Dysfunction in β-cell activity or survival results in diabetes mellitus, a disease affecting millions of Americans with numbers expected to greatly increase. This is creating an enormous economic and health care burden. A future strategy for improving diabetic outcomes will include cell-based therapies wherein functional β-cells are generated to replenish those lost during diabetes progression. Success will require increasing our understanding of the complex transcriptional programs required for establishing and maintaining β-cells during development and in adults, respectively. My lab and others previously demonstrated that the Islet-1 transcription factor is important for islet cell development and function. Furthermore, Islet-1 activity during late phases of β-cell development requires the interacting transcriptional co-regulator, Ldb1. However, little is known of the comparative target genes and pathways governed by these factors. The complexity of Ldb1-mediated complexes also appears greater than simply through Islet-1. For example, our recently published data suggests that Ldb1/Islet-1 complexes are very large, also containing SSBP3, a co-regulator required for Ldb1 complex activity and stability in vitro. This suggests that SSBP3 is a new player in β-cell development and function. Three complementary Aims will define comparative roles of Ldb1 complexes during islet development, and in adult β-cells. Aim 1 will utilize conditional Ldb1 knockout models to test function in pancreatic endocrine progenitor cells and beyond. We will examine how Ldb1 impacts pancreas marker expression, cell proliferation and survival, endocrine cell identity, and islet function. Aim 2 will employ genome-wide next generation sequencing approaches to assess genes controlled by Ldb1 in endocrine progenitors. Results will be compared to Islet-1, as well as Pdx1 and Ngn3, two critical factors in developing islets. Aim 3 will examine the in vivo function of the novel pancreas regulator, SSBP3, during islet development and in adult β-cell function, as compared with known Ldb1 and Islet-1 roles. This proposal will test our central hypothesis that multiple Ldb1 complexes are required throughout pancreatic organogenesis and in adult β-cell function. My extensive experience studying transcription factor complexes and our readily available in vitro and in vivo reagents, make my lab uniquely suited to executing these Aims. Results reported from this proposal will benefit efforts in developing new molecular targets and cell-based therapies to combat diabetes.