Chemical pancreatectomy for chronic pancreatitis and pancreatic cancer

化学胰腺切除术治疗慢性胰腺炎和胰腺癌

• 批准号: 10163180
• 负责人: FARZAD ESNI
• 金额: $ 43.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163180
• 关键词: Ablation; Acetic Acids; Acinus organ component; Address; Adenocarcinoma; Affect; Anatomy; Applications Grants; Area; Ascites; Autologous Transplantation; Behavioral; Beta Cell; Biliary; Cell physiology; Cells; Chemicals; Chronic; Diabetes Mellitus; Disease; Duct (organ) structure; Endocrine; Ethanol; Exocrine pancreas; Functional disorder; Glucagon; Human; Hypoglycemia; Immune; In Situ; Individual; Inflammation; Infusion Technique; Infusion procedures; Injections; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Islets of Langerhans; Lead; Lesion; Life; Ligation; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Medicine; Microanatomy; Mus; Nature; Nerve; Obstruction; Operative Surgical Procedures; Pain; Pain management; Pancreas; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Pathway interactions; Patients; Perfusion; Persistent pain; Positioning Attribute; Procedures; Quality of life; Regimen; Residual state; Risk; Spinal Ganglia; System; Techniques; Therapeutic; Therapeutic Intervention; Therapeutic Trials; Time; Tissues; Total Pancreatectomy; United States; Vertebral column; alcohol effect; capsule; central pain; chronic pain; chronic pancreatitis; experience; experimental study; high risk; human subject; improved; islet; mouse model; neoplastic; nerve supply; nonhuman primate; pancreatic tumorigenesis; peripheral pain; premalignant; preservation; pressure; prevent; success

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.

项目总结/摘要 慢性胰腺炎仅在美国就影响了超过140，000人，全世界有数百万人。 慢性胰腺炎的治疗性干预通常涉及相对无效的疼痛治疗，或高度疼痛治疗。 侵入性和病态的外科手术。慢性胰腺炎引起严重的慢性衰弱性疼痛，伴随沿着 可能危及生命的并发症，如假性囊肿、胰性腹水、胆道梗阻等。 胰腺炎患者发生胰腺导管腺癌的风险大约增加13倍。 此外，不幸的是，大多数慢性胰腺炎患者继续发展为非常脆弱的糖尿病形式， 3c型，在这种情况下，他们不仅失去了胰岛素细胞，而且失去了所有的胰岛细胞，因此他们失去了重要的胰岛素反调节作用。 机制等看来，持续的慢性外分泌损伤为胰岛细胞创造了一个有毒的环境。这种有毒 环境导致进行性胰岛细胞功能障碍和胰岛细胞损失。这些患者的一种治疗策略是 胰岛自体移植胰腺切除术。这个过程是非常病态的，超过一半的原始胰岛 可能会丢失。此外，自体移植的胰岛位于肝脏中，其中β细胞功能显著降低。 与它们在胰腺内的原位功能相比，它们的功能减弱了。最近，我们偶然发现， 将乙醇或乙酸注入小鼠的胰管，导致腺泡和胰管完全消融，但 胰岛完全幸免，并且无限期地正常运作。然后，我们转向一个小鼠模型， 胰腺炎，模仿人类的情况，因为胰岛随着时间的推移而丢失。值得注意的是，通过干预， 我们对患有明确慢性胰腺炎但在明显的胰岛损失之前的小鼠进行乙醇或醋酸输注， 完全和持久的保护胰岛质量。最后，我们开发了一种非胰管灌注系统， 人类灵长类动物，已经允许初步成功与类似的外分泌消融，并与胰岛保存。 在这里，在这个提议中，我们希望更好地了解输注对胰腺的影响。具体来说，详细 分析神经支配（重点是疼痛通路和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。我们将试图了解这些小岛是如何以及为什么幸免于难的， 与最近描述的胰岛“胶囊”有关。我们还将努力在初步尝试的基础上再接再厉， 优化非人类灵长类动物的化学胰腺切除术，使我们更接近人类的治疗试验， 科目最后，针对胰腺癌高危的慢性胰腺炎患者，我们将确定其治疗效果 乙醇或乙酸输注可能对小鼠胰腺的癌前病变和癌症有影响。