Studies of Pancreatic TGFBeta-Mediated Signaling

描述（由申请人提供）： 最近的证据表明，TGF β信号通路的扰动在外科胰腺疾病（包括胰腺癌和胰腺炎）的发展中起着至关重要的作用。然而，人类胰腺中TGF β信号传导的机制在很大程度上是未知的。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，并且反映在目前人类外分泌胰腺癌和胰腺炎的经验性且通常无效的治疗中。最近，我们已经鉴定了胰腺中TGF β的一种新的信号传导途径，其中TGF β信号传导途径的专性第二信使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重要机制。我们的初步数据表明，胰腺腺泡细胞内的Smads和PKA的调节亚基的一种新的相互作用，也表明PICA可能介导的TGF β诱导的生长抑制反应。因此，我们推测TGF对生长的生理作用是由Smads及其与PKA信号通路的相互作用介导的。本研究旨在探讨TGF β 1 3信号分子与PKA信号通路相互作用的分子基础。实验将解决的假设，Smads 3和4直接结合并激活PKA的一个以前未确定的，cAMP-独立的机制，并将确定相互作用域的Smads 3和4和PKA的调节亚基。此外，我们将研究PKA在TGF β介导的胰腺腺泡细胞生长抑制中的作用。拟议的研究将生理学研究与新的分子策略相结合，这种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TGF信号传导机制，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.