Studies of Pancreatic TGFBeta-Mediated Signaling

胰腺 TGFβ 介导的信号传导研究

• 批准号: 6739014
• 负责人: DIANE M SIMEONE
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739014
• 关键词: Adenoviridae; DNA binding protein; acinar cell; biological signal transduction; cell growth regulation; cyclic AMP; endocrine surgery; enzyme activity; enzyme complex; genetically modified animals; immunoprecipitation; laboratory mouse; mass spectrometry; pancreas; pancreas disorder; protein kinase A; protein protein interaction; protein purification; thymidine; tissue /cell culture; transfection /expression vector; transforming growth factors; two dimensional gel electrophoresis

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.

描述（由申请人提供）： 最近的证据表明，TGFBETA信号通路中的扰动在包括胰腺癌和胰腺炎在内的手术胰腺疾病的发展中起着至关重要的作用。然而，人胰腺中TGFBETA信号的机制在很大程度上尚不清楚。缺乏基本信息是对人类胰腺疾病合理治疗的主要障碍，并且反映在当前的经验性治疗中，并且通常无法治疗人类外分泌胰腺癌和胰腺炎。最近，我们确定了TGF的新型信号传导途径[胰腺中的3个，即TGFBETA信号传导途径的第二个使者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，SMADS的新型相互作用和胰腺腺泡细胞中PKA的调节亚基的相互作用，还表明PICA可能介导TGFBETA诱导的生长抑制反应。因此，我们假设TGF对生长的生理影响是由SMAD介导的及其与PKA信号通路的相互作用。该研究建议旨在研究TGFI3信号分子与PKA信号通路相互作用的分子基础。该实验将解决以下假设：SMADS3和4通过先前未鉴定的cAMP独立机制直接与PKA结合并激活PKA，并确定SMADS 3和4的相互作用域以及PKA的调节亚基的相互作用域。此外，我们将研究PKA在胰腺腺泡细胞中TGFBETA介导的生长抑制中的作用。拟议的研究将生理研究与新颖的分子策略相结合，这种方法可能揭示了重要的新见解。该项目的长期目标是详细了解胰腺中TGF信号传导机制，这可能在治疗和/或预防人类胰腺疾病方面受益。