Doctor of Philosophy (PhD)
Type 1 diabetes (T1D) is an autoimmune disease where the immune system targets the pancreatic islet beta-cells, which are responsible for insulin production and secretion, leading to a state of insulin insufficiency. Many of the molecular details of disease onset and progression remain poorly understood, including key aspects of cytokine signaling. Therefore, we have examined some of the consequences of inflammatory cytokine signaling as a critical module relevant to T1D. Using interleukin-1 (IL-1) signaling as a well-defined paradigm for inflammation, we investigated key components of this signaling pathway in pancreatic beta-cells. We identified ICAM-1, one of the proteins expressed in response to IL-1, as an early response gene in pancreatic beta-cells. This is significant because ICAM-1 has an important role in the development of autoimmunity that leads to T1D. First, we review the literature on ICAM-1 in autoimmune diabetes. We then examine the transcriptional mechanisms of Icam1 expression in the beta-cell, with a focus on rapid protein-DNA interactions as well as epigenetic events within the first few hours of cytokine stimulation. We found that IL-1beta activates the NF-kappaB pathway to upregulate the production of ICAM-1 in the beta-cell via binding to specific genomic regulatory sites within its promoter. These discoveries were made using in vitro models, ex vivo rodent and human islets, and autoimmune mouse models. Moreover, the expression of additional IL-1beta-inducible genes were investigated, with a focus on syntaxin 11 (Stx11), another gene rapidly upregulated in pancreatic beta-cells. Stx11, though understood in other physiological contexts, has no known function in beta-cells. The biology of Stx11 to traffic secretory granules in other cell types has major implications for production and release of small proteins from beta-cells; islet beta-cells are known to produce and secrete insulin but are also capable of producing chemokines, which are small secreted proteins that regulate immune cell trafficking. Collectively, the findings presented herein represent novel molecular mechanisms that define how islet beta-cells respond to cytokine signals by altering their genetic program through interaction with the immune system.
Martin, Thomas Malone, "The Regulation of Autoimmunity Genes in Pancreatic β-Cells by NF-κB" (2023). LSU Doctoral Dissertations. 6133.