Imaging zinc secretion from the exocrine pancreas for the early diagnosis of pancreatic adenocarcinoma with MRI

项目总结/摘要 该建议旨在使用无创性分子磁共振（MR）成像胰腺锌含量 胰腺上皮内瘤变（PanIN）是胰腺导管癌的早期癌前病变， 腺癌（PDAC）病变。据估计，美国将有55，440人被诊断患有胰腺癌。 2019年将有45,750人死于这种疾病。目前的诊断技术包括使用成像， 定位病变和侵入性活检取样以分期癌症，并从 肿瘤一旦确诊，治疗选择有限，因为有症状的患者可能已经有了 晚期PDAC因此，需要早期且以非侵入性方式检测PDAC病变。是 已知锌以高水平储存在腺泡细胞中的酶原颗粒中，并且锌稳态是唯一的 在PDAC中失调。我们已经成功地证明，磁共振成像与钆（Gd）基锌传感器， 可以报告作为对雨蛙肽刺激的响应的从胰腺外分泌组织的锌释放。在本提案中，我们 将评估一组促分泌素，这是一种已知的刺激锌分泌的化合物， 外分泌胰腺中的导管和/或腺泡细胞，以优化它们产生锌通量的能力， 分子磁共振探针然后，我将使用这种细胞特异性代谢锌成像技术， 通过MRI观察胰腺癌小鼠模型中锌稳态失调。阐明锌稳态的作用 通过非侵入性测量腺泡和导管细胞锌释放的胰腺癌的发展， 对它们天然促分泌素的反应将使我们能够鉴定出报告分子水平的生物标志物， 疾病早期的转变。这反过来又可以使患者在早期阶段获得诊断， 从而获得更有效的治疗和治愈性手术选择。 该项目的短期目标是优化和表征刺激的锌分泌， 胰腺外分泌及其在体内的分子MRI检测，以识别PDAC的早期恶性转化， 这样做，我将从我的顾问委员会获得培训，他们是胰腺癌领域的专家 分子发病机理、组织病理学、外科学和放射学。实现我的短期目标将使我能够获得 在以下领域具有专长：1）胰腺癌的临床病理诊断技术。（二） 生物标志物鉴定和验证。3)锌稳态在PDAC发病机制中的代谢意义。这 项目还将允许我生成数据，这将提高我成功获得独立NIH的概率 给予支持。通过研究和培训活动获得的技能和知识， 通过这项提议，我将能够实现我的长期目标，成为一名使用MRI的独立翻译研究者， 基于金属稳态推断癌症发病机理关键代谢、生物学和生理学特征。

PROJECT SUMMARY/ABSTRACT This proposal aims to use noninvasive molecular magnetic resonance (MR) imaging of pancreatic zinc content and secretion to detect pancreatic intraepithelial neoplasia (PanIN), as early pre-malignant pancreatic ductal adenocarcinoma (PDAC) lesions. It is estimated that 55,440 people in the US will be diagnosed with pancreatic cancer and 45,750 people will succumb to the disease in 2019. Current diagnostic techniques include the use of imaging to localize a lesion and invasive biopsy sampling to stage the cancer and obtain molecular and cellular information from the tumor. Once diagnosed, there are limited treatment options since symptomatic patients will likely already have advanced stage PDAC. Therefore, there is a need to detect PDAC lesions early and in a non-invasive manner. It is known that zinc is stored in zymogen granules in acinar cells at high levels and that zinc homeostasis is uniquely dysregulated in PDAC. We have successfully demonstrated that MR imaging with gadolinium (Gd)-based zinc sensors can report on zinc release from exocrine pancreatic tissue as a response to caerulein stimulation. In this proposal we will evaluate a panel of secretagogues, which are chemical compounds known to stimulate the secretion of zinc from ductal and/or acinar cells in the exocrine pancreas, to optimize their ability to generate zinc flux detectable with our molecular MR probe. I will then use this cell-specific metabolic zinc imaging technique to noninvasively quantify the zinc homeostatic dysregulation in pancreatic cancer mouse models by MRI. Elucidating the role of zinc homeostasis in the development of pancreatic adenocarcinoma by non-invasively measuring zinc release from acinar and ductal cells as a response to their natural secretagogues will allow us to identify biomarkers that report on molecular transformations early in the disease. This in turn could then enable patients to obtain a diagnosis at an early stage and thus have access to more effective therapies and curative surgical options. The short-term goal of this project is to optimize and characterize the stimulated zinc secretion in the exocrine pancreas and its detection in vivo with molecular MRI to identify early malignant transformations in PDAC, in doing so I will obtain the training from my advisory committee, who are experts in the field of pancreatic cancer molecular pathogenesis, histopathology, surgery, and radiology. Attaining my short-term goal will enable me to obtain expertise in the following areas: 1) Clinical pathology techniques for diagnosis of pancreatic adenocarcinoma. 2) Biomarker identification and validation. 3) Metabolic implications of zinc homeostasis in PDAC pathogenesis. This project will also allow me to generate data that will enhance my probability of success in obtaining independent NIH grant support. With the skills and knowledge obtained as a result of the research and training activities from this proposal, I will be able to reach my long-term goal of becoming an independent translational investigator using MRI to infer key metabolic, biological, and physiological characteristics of cancer pathogenesis based on metal homeostasis.