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

项目摘要/摘要 这项建议旨在使用无创性分子磁共振(MR)成像胰腺锌含量 和分泌物检测胰腺上皮内瘤变(Panin)，作为早期胰腺癌前导管 腺癌(PDAC)病变。据估计，美国将有55440人被诊断出患有胰腺癌 2019年将有45750人死于这种疾病。目前的诊断技术包括使用成像来 定位病变和侵入性活组织检查样本以分期癌症并从 肿瘤。一旦确诊，治疗选择有限，因为有症状的患者很可能已经有了 高级PDAC。因此，有必要以非侵入性方式及早发现PDAC病变。它是 已知锌以高水平储存在腺泡细胞的酶原颗粒中，锌的动态平衡是唯一的 在PDAC中调节失调。我们已经成功地证明了基于Gd(Gd)的锌传感器的磁共振成像 可以报告胰腺外分泌组织对雨蛙素刺激的反应。在这份提案中，我们 将评估一组促分泌剂，这是一种已知的化合物，可以刺激锌的分泌 胰腺外分泌中的导管和/或腺泡细胞，以优化它们产生锌通量的能力 分子磁共振探头。然后我将使用这种细胞特异性代谢锌成像技术来非侵入性地量化 核磁共振研究胰腺癌小鼠模型中锌的稳态失调。阐明锌的动态平衡在蛋白合成中的作用 腺泡和导管细胞锌释放的无创性测定在胰腺癌发生中的作用 对其天然促分泌物的反应将使我们能够识别报告分子的生物标记物 在疾病早期就发生了变化。这反过来又可以使患者在早期阶段获得诊断，并 从而获得更有效的治疗方法和根治性手术选择。 该项目的短期目标是优化和表征被刺激的锌的分泌。 胰腺外分泌及其活体分子磁共振检测对早期胰腺癌恶变的诊断价值 这样，我将从我的顾问委员会那里获得培训，他们是胰腺癌领域的专家。 分子发病机制、组织病理学、外科和放射学。实现我的短期目标将使我能够 擅长以下几个方面：1)胰腺癌的临床病理诊断技术。2) 生物标记物的识别和验证。3)锌稳态在PDAC发病机制中的代谢意义。这 该项目还将允许我生成数据，以提高我获得独立NIH的成功概率 给予支持。利用从研究和培训活动中获得的技能和知识 提议，我将能够实现我的长期目标，成为一名独立的翻译调查员使用MRI来 根据金属动态平衡推断癌症发病的关键代谢、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.