EGF and TGF-β signaling synergy in β-cell proliferation

EGF 和 TGF-β 信号在 β 细胞增殖中的协同作用

• 批准号: 9349505
• 负责人: GEORGE K. GITTES
• 金额: $ 38.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-10 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349505
• 关键词: Agonist; Applications Grants; B Cell Proliferation; Beta Cell; Binding; Cancer cell line; Cell Line; Cytostatics; Data; Diabetes Mellitus; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Future; GCG gene; Goals; Heart; Human; In Vitro; Individual; Laboratories; Lead; Ligands; Ligation; Literature; Mediating; Mediator of activation protein; Mitogens; Modeling; Molecular; Mus; Natural regeneration; Pancreatectomy; Pancreatic duct; Pathway interactions; Patients; Phosphorylation; Play; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Work; analog; base; cancer cell; diabetes mellitus therapy; extracellular; glucagon-like peptide 1; improved; in vivo; inhibitor/antagonist; mouse model; overexpression; programs; synergism

Project Summary and Relevance (Abstract) The overall goal of our research program is to determine the optimal way to induce β-cell proliferation, both in vitro and in vivo, to improve β-cell mass in patients with diabetes mellitus. Over the last several years, we have used various mouse models to study β-cell neogenesis, regeneration, and proliferation. Transforming growth factor beta (TGF-β) signaling, and a key intracellular component of TGF-β signaling, smad7, seem to play an important role in regulating β-cell proliferation. However, apparently inconsistent roles for TGF-β signaling in different models of β-cell proliferation led us to realize that epidermal growth factor (EGF) signaling was also key, and that synergy between EGF signaling and TGF-β signaling was at the heart of inducing optimal β-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-β 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-β receptor signaling, but second, it can also at the same time specifically suppress anti-proliferative (cytostatic) actions of TGF-β receptor signaling. Third, TGF-β 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 β-cell proliferation. In particular, one of the most potent known β-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-β signaling that lead to enhanced β-cell proliferation. Here, we will pursue the possibility that EGF receptor signaling selectively enhances TGF-β receptor pro-proliferative signals, and specifically suppresses anti-proliferative (cytostatic) TGF-β receptor signals, both mediated by smad7. Specific Aim 2: Determine a role for TGF-β signaling and smad7 in enhancing the β-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 β-cell proliferation. In addition, we will study a potential synergistic role for TGF-β receptor signaling specifically in augmenting the powerful GLP-1 mitogenic effect on β-cells, since GLP-1 works through the EGF receptor signaling pathway.

项目摘要和相关性（摘要） 我们研究计划的总体目标是确定体外和体内诱导 β 细胞增殖的最佳方法，以改善糖尿病患者的 β 细胞质量。在过去的几年中，我们使用各种小鼠模型来研究 β 细胞的新生、再生和增殖。转化生长因子 β (TGF-β) 信号传导以及 TGF-β 信号传导的关键细胞内成分 smad7 似乎在调节 β 细胞增殖中发挥着重要作用。然而，不同β细胞增殖模型中TGF-β信号传导的作用明显不一致，这使我们认识到表皮生长因子（EGF）信号传导也是关键，并且EGF信号传导和TGF-β信号传导之间的协同作用是诱导最佳β细胞增殖的核心。我们相信 smad7 是这种协同作用的关键调解者。文献中有充足的证据证明 EGF 信号传导、TGF-β 信号传导和 smad7 之间存在这种协同作用。这种协同作用似乎是通过三种相互作用途径实现的。首先，EGF 受体信号传导可以特异性增强 TGF-β 受体信号传导的促增殖作用，但其次，它还可以同时特异性抑制 TGF-β 受体信号传导的抗增殖（细胞抑制）作用。第三，TGF-β受体信号转导可以反过来增强EGF受体信号转导。在文献中，这些研究通常集中在癌细胞系的增殖上，但在本提案中，根据我们的初步数据，我们希望将这些相同的原理应用于 β 细胞增殖。特别是，最近发现 GLP-1 是已知最有效的 β 细胞有丝分裂剂之一，可通过 EGF 受体信号传导发挥作用。该拨款提案将通过两个具体目标研究这些潜在途径的相互作用。具体目标 1：确定 EGF 受体信号传导诱导 TGF-β 信号传导改变的分子机制，从而导致 β 细胞增殖增强。在这里，我们将探讨 EGF 受体信号传导选择性增强 TGF-β 受体促增殖信号，并特异性抑制抗增殖（细胞抑制）TGF-β 受体信号的可能性，这两种信号均由 smad7 介导。具体目标 2：确定 TGF-β 信号传导和 smad7 在增强 EGF 受体信号传导和 GLP-1 信号传导诱导的 β 细胞增殖中的作用。在这里，我们将完善我们假设有助于最佳 β 细胞增殖的三个协同途径。此外，我们将研究 TGF-β 受体信号传导的潜在协同作用，特别是在增强 GLP-1 对 β 细胞的强大促有丝分裂作用方面，因为 GLP-1 通过 EGF 受体信号传导途径发挥作用。