Molecular Mechanisms of Pain in Chronic Pancreatitis

描述（由申请人提供）：慢性胰腺炎仍然是一种常见且具有挑战性的临床综合征。它的主要特征是疼痛，尽管有许多经验治疗方法，但很难有效治疗。十多年来，我们的实验室一直在积极探索胰腺炎疼痛的分子发病机制。在此过程中，我们建立了非常有用和相关的啮齿动物CP模型，并对特定分子，特别是电压依赖性（Kv）和TRPV1离子通道以及神经生长因子（NGF）的贡献获得了有价值的见解。然而，很明显，我们需要学习的还有很多。在本提案中，我们将重点关注转化生长因子β (TGF?)在慢性炎症性疼痛发病机制中的作用。尽管TGF吗?在炎症环境中表现突出，但其对伤害致敏的参与很少受到关注。我们的假设是TGF？是感觉神经元功能的重要调节剂，通过改变胰腺特异性感觉神经元兴奋性和离子通道功能，在慢性胰腺炎疼痛的发病机制中起重要作用。在本提案中，我们将尝试通过包括分子，电生理和行为分析在内的综合多学科方法来证明这一假设，具体目的如下：(1)确定TGF？(2)外源性TGF？(3)内源性TGF？慢性胰腺炎疼痛行为和感觉神经元可塑性的发病机制。这一建议的意义是双重的。首先，它将更好地了解慢性胰腺炎疼痛的发病机制。其次，它将为TGF？这为其参与许多其他慢性疼痛疾病提供了可能性，这些疾病可能是炎症性或肿瘤性的。

DESCRIPTION (provided by applicant): Chronic pancreatitis remains a common and challenging clinical syndrome. Its cardinal feature, pain, has been difficult to treat effectively despite a multitude of empirical therapeutic approaches. Our laboratory has been actively pursuing the molecular pathogenesis of pain in pancreatitis for over a decade. In the process we have established highly useful and relevant rodent models of CP and gained valuable insight into the contribution of specific molecules, particularly voltage dependent (Kv) and TRPV1 ion channels and nerve growth factor, NGF. However, it is clear that there is much more that we need to learn. In this proposal, we will focus on a previously under scribed role of transforming growth factor beta, (TGF?) in the pathogenesis of chronic inflammatory pain. Although TGF? is prominent in the inflammatory mileu, its participation in nociceptive sensitization has received little attention. Our hypothesis is that TGF? is an important modulator of sensory neuronal function and plays a major role in the pathogenesis of pain in chronic pancreatitis via changes in pancreas-specific sensory neuronal excitability and ion channel function. In this proposal, we will attempt to prove this hypothesis, using a comprehensive multidisciplinary approach encompassing molecular, electrophysiological and behavioral assays, via the following specific aims: (1) To determine the effects of TGF? on sensory neuronal excitability and ion channel activity in vitro (2) To determine the effects of exogenous TGF? on pain behavior and pancreatic sensory neuronal plasticity (in vivo) (3)To determine the role of endogenous TGF? in the pathogenesis of pain behavior and sensory neuronal plasticity in chronic pancreatitis. The significance of this proposal is two-fold. First, it will provide a better understanding of the pathogenesis of pain in chronic pancreatitis. Secondly, it will establish a major new biological role for TGF?, opening up the possibility of its involvement in many other chronic painful disorders that may be inflammatory or neoplastic in origin.