Chemical pancreatectomy for chronic pancreatitis and pancreatic cancer

项目摘要/摘要 慢性胰腺炎仅在美国就影响到14万多人，全世界有数百万人受到影响。 慢性胰腺炎的治疗干预通常包括相对无效的疼痛治疗，或高度 侵入性和病态的外科手术。慢性胰腺炎导致严重的慢性衰弱疼痛，以及 可能危及生命的并发症，如假性囊肿、胰性腹水、胆道梗阻等 胰腺炎患者患胰腺导管腺癌的风险大约增加了13倍。 此外，不幸的是，大多数慢性胰腺炎患者继续发展为一种非常脆弱的糖尿病， 3c型，在这种情况下，它们不仅失去胰岛素细胞，而且失去所有的胰岛细胞，从而失去重要的胰岛素逆调节作用 机械装置。看来，正在进行的慢性外分泌损伤为胰岛细胞创造了一个有毒的环境。这是有毒的 环境导致进行性胰岛细胞功能障碍和胰岛细胞丢失。针对这些患者的一种治疗策略是 胰腺切除联合自体胰岛移植。这一过程非常病态，超过一半的原始胰岛 可能会迷失。此外，自体移植的胰岛位于肝脏，在那里β细胞功能显著。 与它们在胰腺内的原位功能相比减弱。最近，我们偶然发现一种输液 无论是乙醇还是醋酸进入小鼠的胰管，都会导致腺泡和胰管完全消融，但 胰岛完全幸免于难，功能正常，无限期。然后我们转向慢性阻塞性肺疾病的小鼠模型 一种模拟人类情况的胰腺炎，胰岛会随着时间的推移而消失。值得注意的是，通过干预 乙醇或醋酸输注在慢性胰腺炎小鼠中的作用，但在显著的胰岛丢失之前，我们 锯切完整耐用的胰岛包块保护。最后，我们研制了一种非胰管输液系统。 人类灵长类动物在类似的外分泌消融和胰岛保存方面取得了初步成功。 在这里，在这项建议中，我们希望更好地了解输液对胰腺的影响。具体地说，详细的 分析神经支配(重点是疼痛通路以及外周和中枢疼痛敏感化)、免疫细胞和 炎症，以及对疼痛的影响。也许，我们将试图了解这些小岛是如何以及为什么幸免的。 与最近描述的胰岛“胶囊”有关。我们还将努力在我们初步尝试的基础上再接再厉 在非人类灵长类动物中优化这种化学胰腺切除术，使我们更接近在人类身上进行治疗试验 研究对象。最后，由于慢性胰腺炎患者患胰腺癌的风险很高，我们将确定 乙醇或醋酸输注可能会对小鼠的癌前病变和胰腺癌产生影响。

Project Summary/Abstract Chronic pancreatitis affects more than 140,000 individuals in the United States alone, and millions world-wide. Therapeutic interventions for chronic pancreatitis typically involve either relatively ineffective pain treatments, or highly invasive and morbid surgical procedures. Chronic pancreatitis entails severe, chronic debilitating pain, along with potentially life-threatening complications such as pseudocyst, pancreatic ascites, biliary obstruction, etc. Chronic pancreatitis patients have a roughly 13-fold increased risk of developing pancreatic ductal adenocarcinoma. Furthermore, unfortunately most chronic pancreatitis patients go on to develop a very brittle form of diabetes mellitus, type 3c, in which they lose not only insulin cells, but all islet cells, so that they lose important insulin counter-regulatory mechanisms. It appears that the ongoing chronic exocrine damage creates a toxic milieu for the islet cells. This toxic milieu leads to progressive islet cell dysfunction and islet cell loss. One therapeutic strategy for these patients is a total pancreatectomy with islet autotransplantation. This procedure is highly morbid, and more than half of the original islets can be lost. In addition, the autotransplanted islets are situated in the liver, where beta cell function is significantly diminished compared to their function in situ within the pancreas. Recently, we serendipitously found that an infusion of either ethanol or acetic acid into the pancreatic duct of mice led to complete ablation of the acini and ducts, but the islets were completely spared, and functioned normally and indefinitely. We then turned to a mouse model of chronic pancreatitis that mimics the human condition in that the islets are lost over time. Remarkably, by intervening with an ethanol or acetic acid infusion in mice with well-established chronic pancreatitis, but prior to significant islet loss, we saw complete and durable protection of the islet mass. Lastly, we developed a pancreatic duct infusion system in non- human primates that has allowed for preliminary success with a similar exocrine ablation, and with islet preservation. Here, in this proposal we wish to better understand what the infusion is doing to the pancreas. Specifically, a detailed analysis of innervation (with a focus on pain pathways and peripheral and central pain sensitization), immune cells and inflammation, and the effect on pain experienced. We will try to understand how and why the islets are spared, perhaps related to the islet “capsule” that has been recently described. We will also strive to build on our preliminary attempts to optimize this chemical pancreatectomy in non-human primates to bring us closer to therapeutic trials in human subjects. Lastly, with the high risk of pancreatic cancer in chronic pancreatitis patients, we will determine what effect ethanol or acetic acid infusion may have on pre-cancerous lesions and cancers of the pancreas in mice.