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.

项目摘要/摘要 仅在美国，慢性胰腺炎就会影响超过140,000个人，并且在全球范围内影响了数百万人。 慢性胰腺炎的治疗干预措施通常涉及相对无效的疼痛治疗或高度 侵入性和病态的手术程序。慢性胰腺炎进入股严重，慢性使人衰弱的疼痛以及 潜在的威胁生命的并发症，例如假囊肿，胰腺腹水，胆道梗阻等。慢性 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都会发展出一种非常脆弱的糖尿病形式， 3C型，其中它们不仅失去胰岛素细胞，而且所有胰岛细胞，从而失去重要的胰岛素反调节性 机制。看来，持续的慢性外分泌损伤为胰岛细胞造成了有毒环境。这种有毒 环境导致胰岛细胞功能障碍和胰岛细胞损失。这些患者的一种理论策略是 胰岛切除术和胰岛自动移植。此过程高度病态，超过一半的原始胰岛 可能会丢失。另外，自动移植的胰岛位于肝脏功能明显的肝脏中 与胰腺内的原位功能相比，它们的功能减少。最近，我们偶然发现了 乙醇或乙酸进入小鼠的胰管导致乙酸和管道的消融，但是 胰岛完全幸免，并无限期地运行。然后，我们转向了慢性的鼠标模型 模仿人类状况的胰腺炎，因为胰岛会随着时间的流逝而流失。值得注意的是，通过干预 患有良好成熟的慢性胰腺炎的小鼠中的乙醇或乙酸输注，但在大量胰岛损失之前，我们 看到胰岛质量的完整而耐用的保护。最后，我们在非 - 人类的素数可以通过类似的外分泌消融和胰岛保存获得初步成功。 在这里，在此提案中，我们希望更好地了解输液对胰腺的作用。具体来说，详细 神经支配分析（侧重于疼痛途径，周围和中央疼痛敏感性），免疫电池和 炎症以及对疼痛的影响。我们将尝试了解胰岛如何以及为什么幸免的原因，也许 与最近描述的胰岛“胶囊”有关。我们还将努力建立我们的初步尝试 优化非人类私人的化学胰腺切除术，使我们更接近人类的治疗试验 主题。最后，由于慢性胰腺炎患者患胰腺癌的高风险，我们将确定什么作用 乙醇或乙酸输注可能对小鼠胰腺的癌性病变和癌症进行。