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

通过 MRI 对胰腺外分泌锌分泌进行成像以早期诊断胰腺腺癌

• 批准号: 10055487
• 负责人: Maria Veronica Clavijo Jordan
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-14 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055487
• 关键词: Acinar Cell; Advisory Committees; Age; Area; Benign; Biological; Biological Markers; Biopsy Specimen; Blinded; Caerulein; Cancer Etiology; Cell membrane; Cells; Cessation of life; Characteristics; Chemicals; Clinic; Clinical Pathology; Data; Desmoplastic; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Differential Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Duct (organ) structure; Ductal Epithelial Cell; Early Diagnosis; Endocrine; Exhibits; Exocrine pancreas; Gadolinium; Goals; Grant; Histopathology; Homeostasis; Human; Image; Imaging Techniques; Immunohistochemistry; Implant; Incubated; Individual; Inflammation; Islets of Langerhans; KPC model; Knowledge; Lesion; Location; Magnetic Resonance; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Metals; Molecular; Monitor; Mus; Non-Malignant; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Exocrine Secretion; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathogenesis; Pathologic; Patients; Pharmacology; Physiological; Positioning Attribute; Probability; Prostate; Protocols documentation; Radiology Specialty; Reporting; Research; Research Activity; Research Personnel; Roentgen Rays; Role; Secretin; Sensitivity and Specificity; Signal Transduction; Specificity; Survival Rate; Techniques; Testing; Tissues; Training; Training Activity; Transgenic Organisms; United States; United States National Institutes of Health; Work; Zinc; Zymogen Granules; base; biomarker identification; biomarker validation; cancer cell; career; effective therapy; fluorescence imaging; human tissue; imaging modality; implantation; in vivo; in vivo evaluation; mouse model; optical sensor; pancreas development; pancreas imaging; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; pancreatic juice; premalignant; response; screening; sensor; skills; success; translational scientist; tumor; zinc-binding protein

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.

项目摘要/摘要 该建议旨在使用胰锌含量的无创分子磁共振（MR）成像 检测胰腺内肿瘤（PANIN）的分泌物，作为早期恶性导管 腺癌（PDAC）病变。据估计，美国有55,440人将被诊断出患有胰腺癌 2019年，有45,750人将屈服于该疾病。当前的诊断技术包括使用成像 将病变和侵入性活检采样定位，以分阶段癌症并从中获得分子和细胞信息 肿瘤。一旦诊断出治疗方案有限，因为有症状的患者可能已经有 高级阶段PDAC。因此，有必要早期和非侵入性检测PDAC病变。这是 知道锌在高水平的腺泡细胞中存储在酶原颗粒中，并且锌稳态是独特的 在PDAC中失调。我们成功证明了MR成像使用Gadolinium（GD）的锌传感器 可以报​​告从外分泌胰腺组织中释放锌作为对钙蛋白酶刺激的反应。在这个建议中，我们 将评估一组促囊，该小组是已知的化合物，可刺激锌的分泌 外分泌胰腺中的导管和/或腺泡细胞，以优化它们生成可检测到的锌通量的能力 分子MR探针。然后，我将使用这种细胞特异性的代谢锌成像技术来无创量化 MRI中胰腺癌小鼠模型中的锌稳态失调。阐明锌稳态在 通过非侵入性测量从腺泡和导管细胞释放的锌释放的胰腺腺癌的发展 对其自然秘密的反应将使我们能够识别出报告分子的生物标志物 疾病早期的转变。然后，这可以使患者在早期诊断和 因此，可以使用更有效的疗法和治疗性手术选择。 该项目的短期目标是优化和表征该项目的刺激锌分泌 外分泌胰腺及其在分子MRI的体内检测，以鉴定PDAC的早期恶性转化， 这样做，我将从我的咨询委员会那里获得培训，这些委员会是胰腺癌领域的专家 分子发病机理，组织病理学，手术和放射学。达到我的短期目标将使我能够获得 以下领域的专业知识：1）用于诊断胰腺腺癌的临床病理技术。 2） 生物标志物识别和验证。 3）锌稳态在PDAC发病机理中的代谢意义。这 项目还将允许我生成数据，以提高我在获得独立NIH方面成功的可能性 赠款支持。由于研究和培训活动获得了技能和知识 提案，我将能够实现我的长期目标，即使用MRI成为独立的翻译调查员 推断基于金属稳态的癌症发病机理的主要代谢，生物学和生理特征。