Anti-inflammatory actions of bone morphogenetic protein signaling in the stomach

描述（由申请方提供）：已知慢性炎症状态的存在会引起维持胃粘膜正常形态和功能特征的调节机制紊乱，导致胃炎、消化性溃疡和胃癌等疾病的发生。这些疾病的发病机制中涉及的因素只有部分特征。骨形态发生蛋白（BMP）是一种对胃肠道组织的生长和分化具有重要作用的调节肽。此外，BMP已被证明在肠道中发挥抗炎作用，这表明它们可能代表新颖的且迄今为止特征不佳的胃肠道炎症调节剂。目前尚不清楚胃中BMP介导抗炎作用的机制。在一系列的初步研究中，我们观察到，炎症刺激，如幽门螺杆菌（Hp）和INF-3诱导BMP-4的表达在体内和体外，支持的概念，BMP-4参与调节胃炎症。我们还注意到BMP抑制剂头蛋白在小鼠胃中的转基因表达导致细胞因子如MIP-2、INF-3和TNF-1的表达增加，并导致激酶如ERK和JNK的活化增强，这些激酶参与促炎机制的调节。这些发现的相关性通过观察到转基因小鼠感染Hp导致比非转基因的、年龄匹配的同窝出生的小鼠发生更大的炎症变化而得到强调。最后，在一系列体外研究中，我们注意到BMP-2、BMP-4和BMP-7对犬壁细胞和粘液细胞培养物中的基础和TNF-1刺激的IL-8基因表达发挥直接的抑制作用。基于这些观察，我们假设BMP在胃中发挥抗炎作用，并且BMP信号传导的缺乏导致更显著和强烈的炎症变化的发展。因此，本申请的总体目标是通过使用体内和体外方法来研究BMP信号传导在调节胃中的炎症机制中的功能和作用机制。在第一个具体的目标，我们将测试的假设，炎症刺激，如Hp，IFN-3和TNF-1调节BMP在体内的表达，这一事件可能代表一个自我安全的机制，下调炎症反应的强度。在第二个目标中，我们将阐明BMP信号在体内炎症反应的调节中的作用，通过用炎症刺激物攻击noggin转基因小鼠。在第三个目标中，我们将集中在BMP信号传导对IL-8在分离的壁细胞和粘液细胞的培养物中的表达的作用。通过拟议的研究，我们希望能够提供新的见解，这些见解将对临床医学产生重大影响，因为我们的发现可能有助于更好地了解消化性溃疡和胃癌等疾病的病理生理学。 公共卫生相关性： 通过拟议的研究，我们希望能够提供新的见解，这将对临床医学产生重大影响，因为我们的发现可能有助于更好地了解消化性溃疡和胃癌等疾病的病理生理学。

DESCRIPTION (provided by applicant): The presence of chronic inflammatory states is known to cause perturbations in the regulatory mechanisms that maintain the normal morphological and functional features of the gastric mucosa, leading to the development of diseases such as gastritis, peptic ulcer and gastric cancer. The factors involved in the pathogenesis of these conditions have been only partially characterized. The bone morphogenetic proteins, (BMP) s are regulatory peptides that exert important actions on the growth and differentiation of gastrointestinal tissues. In addition, the BMPs have been shown to exert anti-inflammatory actions in the gut, suggesting that they might represent novel and hitherto poorly characterized regulators of gastrointestinal inflammation. The mechanisms mediating the anti-inflammatory actions of the BMPs in the stomach are currently unknown. In a series of preliminary studies we observed that inflammatory stimuli such as Helicobacter pylori (Hp) and INF-3 induce the expression of BMP-4 both in vivo and in vitro, supporting the notion that BMP-4 is involved in the regulation of gastric inflammation. We also noted that transgenic expression of the BMP inhibitor noggin in the mouse stomach, leads to increased expression of cytokines, such as MIP-2, INF-3 and TNF-1, and to enhanced activation of kinases, such as the ERKs and the JNKs, which are involved in the regulation of pro- inflammatory mechanisms. The relevance of these findings was underscored by the observation that infection of the transgenic mice with Hp, leads to the development of greater inflammatory changes than in non- transgenic, age matched, littermates. Finally, in a series of in vitro studies, we noted that BMP-2, BMP-4 and BMP-7 exert direct, inhibitory actions on both basal and TNF-1-stimulated IL-8 gene expression in cultures of canine parietal and mucus cells. On the basis of these observations we hypothesize that the BMPs exert anti- inflammatory actions in the stomach and that lack of BMP signaling leads to the development of more dramatic and intense inflammatory changes. Accordingly, the overall goal of this application is to investigate the function and the mechanisms of actions of BMP signaling in the regulation of inflammatory mechanisms in the stomach, by using both in vivo and in vitro approaches. In the first specific aim we will test the hypothesis that inflammatory stimuli such as Hp, IFN-3 and TNF-1 regulate BMP expression in vivo and that this event might represent a self-safe mechanism that down-regulates the intensity of the inflammatory response. In the second aim, we will elucidate the role of BMP signaling in the regulation of the inflammatory response in vivo, by challenging the noggin transgenic mice with the inflammatory stimuli. In the third aim, we will focus on the actions of BMP signaling on the expression of IL-8 in cultures of isolated parietal and mucus cells. Through the proposed studies, we expect to shed new insights that will have significant implications in clinical medicine since our discoveries may contribute to a better understanding of the pathophysiology of diseases such as peptic ulcer and gastric cancer. PUBLIC HEALTH RELEVANCE: Project Narrative Through the proposed studies, we hope to shed new insights that will have significant implications in clinical medicine since our findings may contribute to a better understanding of the pathophysiology of diseases such as peptic ulcer and gastric cancer.