Metabonomics Studies of Human Diseases

描述(由申请人提供)：这项为期三年的地区资助申请的总体目标是通过在基于核磁共振和MS的代谢组学研究中建立一个强大的项目来改善迈阿密大学的学术和研究环境，以发现人类疾病的代谢生物标记物。这项研究项目的具体科学目标将是应用代谢图谱来发现早期发现胰腺癌的生物标记物。超过85%的致命人类胰腺肿瘤起源于胰腺的导管上皮细胞。代谢图谱将应用于从胰腺癌小鼠模型收集的尿液和粪便提取物，该模型概括了在人类中观察到的癌前导管肿瘤和肿瘤进展的全谱。我们预测，在mPanIN启动过程中，导管上皮细胞的转化将产生一种代谢特征，这种代谢特征将在尿液和粪便提取物中检测到。由于目前还不可能在Panin阶段检测到人类胰腺癌，我们只能检验这一假设，并使用这个小鼠模型研究Panin启动的最早代谢特征。因此，只有使用小鼠模型来概括Panin启动和肿瘤进展的整个过程，才有可能实现该提案中概述的目标。为了使这项研究与了解人类胰腺癌的发生和发展最相关，有必要研究一种能够紧密复制人类胰腺癌侵袭前病变和肿瘤全谱的小鼠模型。我们将在这项研究中使用的最好的小鼠模型(特定目标#1)是Pdx1-cre；LSL-KrasG12D转基因品系，它已经被很好地描述并概括了在人类观察到的侵袭前胰腺上皮内肿瘤的全部范围。Pdx1-cre；LSL-KrasG12D株在4-6个月龄时发展为mPanIN的高发病率，在6-12个月龄时，许多mPanIN转化为侵袭性胰腺癌。该项目的主要目标将是进行一项为期一年的纵向平行代谢组学和核磁共振研究，以确定是否可以发现用于胰腺癌早期检测的代谢特征生物标记物(特定目标#4)。特定目标#4的成功将需要对小鼠胰腺的MRI图像进行准确和可靠的解释。为了促进这一目标，我们概述了一项“路线图”任务，以在小鼠胰腺的传统组织学背景下解释MRI和MRJ图像(具体目标3)。最后，考虑到小鼠胰腺的复杂性，以及大多数胰腺肿瘤起源于导管上皮这一事实带来的挑战，我们概述了一项任务，即开发和演示针对胰腺导管上皮的新型超顺磁性抗体造影剂的使用，以最大限度地提高MRI图像检测的灵敏度和准确性(特定目标#2)。 公共卫生相关性：胰腺癌在美国每年导致超过3.5万人死亡，是美国癌症死亡的第四大原因，是最致命的癌症形式，约70%的人在首次诊断后4-6个月内死亡，五年生存率不到5%。这种黯淡的前景是因为胰腺癌通常在扩散之前不会被发现，不能再通过手术治疗。提高胰腺癌存活率的最好机会是及早发现，但目前还没有有效的生物标志物来进行早期检测。这项提议的目标是利用一种新的代谢图谱技术来发现新的生物标志物，用于胰腺癌的早期检测，如果成功，这将提高每年数千美国人的生存和生活质量。

DESCRIPTION (provided by applicant): An overall goal of this three-year AREA grant application is to enhance the academic and research environment at Miami University by establishing a strong program in NMR- and MS-based metabonomics research for discovery of metabolic biomarkers for human diseases. The specific scientific goal of this research project will be to apply metabolic profiling to discover biomarkers for early detection of pancreatic cancer. More than 85% of lethal human pancreatic tumors originate in the ductal epithelia of the pancreas. Metabolic profiling will be applied to urine and fecal extracts collected from a mouse model for pancreatic cancer that recapitulates the full spectrum of pre-cancerous ductal neoplasias and tumor progression observed in humans. We predict that transformation of ductal epithelial cells during mPanIN initiation will generate a metabolic signature that will be detectable in urine and fecal extracts. Since it is currently not possible to detect human pancreatic cancer at the PanIN stage, we can only test this hypothesis and investigate the earliest metabolic signatures of PanIN initiation using this mouse model. Therefore, achieving the goals outlined in this proposal will only be possible using a mouse model that recapitulates the entire progression of PanIN initiation and tumor progression. In order that this study be most relevant to understanding initiation and progression of human pancreatic cancer, it is necessary to investigate a mouse model that closely reproduces the full spectrum of pre-invasive lesions and tumors that occur in human pancreatic cancer. The best mouse model available, which we will use in this study (Specific Aim #1) is the Pdx1-cre;LSL-KrasG12D transgenic strain, which has been well characterized and recapitulates the full range of pre- invasive pancreatic intraepithelial neoplasias observed in humans. The Pdx1-cre;LSL-KrasG12D strain develops a high incidence of mPanIN's by age 4-6 months and by the age of 6-12 months many of these mPanIN's transform to invasive pancreatic adenocarcinomas. The main goal of this project will be to conduct a 1-year-long longitudinal parallel metabonomics and MRI study to determine if a metabolic profiling biomarker can be discovered for early detection of pancreatic cancer (Specific Aim #4). The success of specific aim #4 will require accurate and reliable interpretation of MRI images of the mouse pancreas. To facilitate this goal, we have outlined a "road mapping" task to train to interpret MRI and MRJ images in the context of conventional histologies of the mouse pancreas (Specific Aim #3). Finally, given the complexity of the mouse pancreas, and the challenge presented by the fact that the majority of pancreatic tumors originate in the ductal epithelia, we have outlined a task to develop and demonstrate use of novel superparamagnetic antibody contrast agents targeted specifically to the pancreas ductal epithelia to maximize sensitivity and accuracy of detection in MRI images (Specific Aim #2). PUBLIC HEALTH RELEVANCE: Pancreatic cancer kills more than 35,000 individuals in the United States each year, is the fourth leading cause of cancer death in the USA, and is the most lethal form of cancer with about 70% of individuals dying within 4-6 months of initial diagnosis, and the five- year survival rate is less than 5%. The dismal outlook is because pancreatic cancer is usually not detected until it has spread and can no longer be treated by surgery. The best chance for improved survival of pancreatic cancer is early detection, but there are currently no effective biomarkers for early detection. The goal of this proposal is to use a novel technology of metabolic profiling to discover new biomarkers for early detection of pancreatic cancer, which if successful, could improve the survival and quality of life for thousands of Americans each year.