Studies of Pancreatic TGFBeta-Mediated Signaling

描述(由申请人提供)： 最近的证据表明，转化生长因子β信号通路的紊乱在外科胰腺疾病的发展中起着至关重要的作用，包括胰腺癌和胰腺炎。然而，转化生长因子β信号在人胰腺中的作用机制尚不清楚。这种基本信息的缺乏是合理治疗人类胰腺疾病的主要障碍，这反映在目前对人类外分泌性胰腺癌和胰腺炎的经验性治疗，而且往往无效。最近，我们在胰腺中发现了一条新的转化生长因子[3]信号通路，即转化生长因子β信号通路的专有第二信使Smads激活胰腺腺泡细胞中的蛋白激酶A(PKA)。这可能代表了腺泡细胞内串扰的一种重要机制。我们的初步数据表明，Smads与胰腺腺泡细胞内PKA的调节亚基之间存在一种新的相互作用，并提示PICA可能介导了TGFβ诱导的生长抑制反应。因此，我们假设转化生长因子对生长的生理效应是通过Smads及其与PKA信号通路的相互作用来实现的。本研究旨在探讨TGFI3信号分子与PKA信号通路相互作用的分子基础。这些实验将解决这样的假设，即Smads3和4通过一种先前未知的cAMP非依赖机制直接与PKA结合并激活PKA，并将确定Smad3和Smad4的相互作用结构域以及PKA的调节亚单位。此外，我们还将研究PKA在转化生长因子β介导的胰腺腺泡细胞生长抑制中的作用。这项拟议的研究将生理学研究与新的分子策略相结合，这一方法可能会揭示重要的新见解。该项目的长期目标是详细了解胰腺中的转化生长因子信号机制，这可能有助于治疗和/或预防人类胰腺疾病。

DESCRIPTION (provided by applicant): Recent evidence indicates that perturbations in the TGFbeta signaling pathway plays a crucial role in the development of surgical pancreatic disease, including pancreatic cancer and pancreatitis. However, the mechanisms of TGFbeta signaling in the human pancreas are largely unknown. This lack of basic information is a major obstacle to rational treatment of human pancreatic diseases, and is reflected in the current empiric, and often ineffective treatment of human exocrine pancreatic cancer and pancreatitis. Recently, we have identified a novel signaling pathway for TGF[3 in the pancreas whereby the obligate second messengers of the TGFbeta signaling pathway, the Smads, activate protein kinase A (PKA) in pancreatic acinar cells. This may represent an important mechanism of crosstalk within the acinar cell. Our preliminary data demonstrates a novel interaction of Smads and the regulatory subunit of PKA within pancreatic acinar cells, and also suggests that PICA may mediate growth inhibitory responses induced by TGFbeta. Therefore we hypothesize that TGF's physiological effects on growth are mediated by Smads and their interactions with the PKA signaling pathway. This research proposal is designed to investigate the molecular basis for the interaction of TGFI3 signaling molecules with the PKA signaling pathway. The experiments will address the hypothesis that Smads3 and 4 directly bind to and activate PKA by a previously unidentified, cAMP-independent mechanism, and will determine interaction domains of Smads 3 and 4 and the regulatory subunit of PKA. In addition, we will investigate the role of PKA in TGFbeta-mediated growth inhibition in pancreatic acinar cells. The proposed research integrates physiological studies with novel molecular strategies, an approach likely to reveal important new insights. The long term goal of this project is to gain a detailed understanding of TGF signaling mechanisms in the pancreas that may be of benefit in the treatment and/or prevention of human pancreatic disease.