and Relevance (Abstract) The overall goal of our research program is to determine the optimal way to induce ?-cell proliferation, both in vitro and in vivo, to improve ?-cell mass in patients with diabetes mellitus. Over the last several years, we have used various mouse models to study ?-cell neogenesis, regeneration, and proliferation. Transforming growth factor beta (TGF-?) signaling, and a key intracellular component of TGF-? signaling, smad7, seem to play an important role in regulating ?-cell proliferation. However, apparently inconsistent roles for TGF-? signaling in different models of ?-cell proliferation led us to realize that epidermal growth factor (EGF) signaling was also key, and that synergy between EGF signaling and TGF-? signaling was at the heart of inducing optimal ?-cell proliferation. We believe that smad7 is a key mediator of this synergy. There is ample evidence in the literature for such synergy between EGF signaling, TGF-? signaling, and smad7. This synergy appears to come through three pathways of interaction. First, EGF receptor signaling can specifically enhance pro-proliferative aspects of TGF-? receptor signaling, but second, it can also at the same time specifically suppress anti-proliferative (cytostatic) actions of TGF-? receptor signaling. Third, TGF-? receptor signaling can in turn enhance EGF receptor signaling. In the literature these studies are generally focused on the proliferation of cancer cell lines, but here in this proposal, based on our preliminary data, we wish to apply these same principles to ?-cell proliferation. In particular, one of the most potent known ?-cell mitogens, GLP-1, was recently found to work through EGF receptor signaling. This grant proposal will study these potential pathway interactions through two Specific Aims.
Specific Aim 1 : Determine molecular mechanisms for EGF receptor signaling-induced alterations in TGF-? signaling that lead to enhanced ?-cell proliferation. Here, we will pursue the possibility that EGF receptor signaling selectively enhances TGF-? receptor pro-proliferative signals, and specifically suppresses anti-proliferative (cytostatic) TGF-? receptor signals, both mediated by smad7.
Specific Aim 2 : Determine a role for TGF-? signaling and smad7 in enhancing the ?-cell proliferation induced by EGF receptor signaling and by GLP-1 signaling. Here, we will round out the three synergistic pathways that we hypothesized contribute to optimal ?-cell proliferation. In addition, we will study a potential synergistic role for TGF-? receptor signaling specifically in augmenting the powerful GLP-1 mitogenic effect on ?-cells, since GLP-1 works through the EGF receptor signaling pathway.
A better understanding of ?-cell proliferation in vivo is one of the most important goals in our quest for a cure for diabetes mellitus. TGF-? signaling and the downstream mediators, the smads, have been implicated in the regulation of ?-cell proliferation. We have found that TGF-? and EGF signaling seem to synergize to induce a robust ?-cell proliferation. This synergy seems to hinge on the action of intracellular mediators, the smads, which classically have been thought to respond only to TGF-? signaling. Here we propose to study the inner workings behind the TGF-?/EGF synergy, and likely the involvement of other signaling pathways that may impinge on signaling. The proposed work will strive to better understand the contribution of the individual TGF-? and EGF pathways to the synergistic induction of ?-cell proliferation. In addition, we will attempt to dissect out the exact phosphorylation pathway for the smads that results in this synergy. Lastly, we will investigate the detailed function and interactions of an apparent master regulator of ?-cell proliferation, smad7.
| Xiao, Xiangwei; Guo, Ping; Shiota, Chiyo et al. (2018) Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes. Cell Stem Cell 22:78-90.e4 |
| Xiao, Xiangwei; Fischbach, Shane; Zhang, Tina et al. (2017) SMAD3/Stat3 Signaling Mediates ?-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis-Related Diabetes. Diabetes 66:2646-2658 |
| Shiota, Chiyo; Prasadan, Krishna; Guo, Ping et al. (2017) Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells. Diabetologia 60:2399-2408 |
| Sheng, Qingfeng; Xiao, Xiangwei; Prasadan, Krishna et al. (2017) Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet. Sci Rep 7:16348 |
