Characterization of the Molecular Determinants of High-Grade Dysplasia in Pancreatic Cancer Precursor Lesions

该提案描述了一项研究计划和培训计划，以培养首席研究员Dr。 劳拉·伍德，从初级教员变成了一名独立的内科科学家。伍德博士已经完成了 在癌症基因组学方面具有开创性的工作，并已完成胃肠道、肝脏和 胰腺病理学。2013年7月，她被任命为助理教授，这是一个终身教职职位 75%的保护时间用于建议的研究。她的长期目标是发展一项独立的研究 描述胰腺多步骤肿瘤发生的分子事件的程序。 这项计划将利用她在基因组学和胰腺病理学方面的现有专业知识；然而，它将 还需要生物信息学和细胞生物学方面的额外培训，以便独立识别和 从功能上验证胰腺肿瘤的分子事件。为了实现这些目标，Dr。 伍德组建了一个多元化的指导团队，拥有癌症基因组学、胰腺癌基因组学方面的专业知识 病理学、细胞生物学和生物信息学。她的职业发展计划包括正式的课程学习 以及研讨会、实验室会议和动手培训。拟议的研究和职业发展 将指导伍德博士担任领导一个富有成效的独立研究小组的职位。 侵袭性胰腺癌源于非侵袭性癌前病变，如果发现这些病变是可以治愈的。 已经够早了。这些先兆包括低级别病变(恶性风险较低 高级别病变(相当于原位癌)。早些时候 高级别前体癌变前的检测是提高疗效的关键 胰腺肿瘤患者的存活率。尽管临床上很重要，但人们对此知之甚少。 区分胰腺中低级别和高级别前体的变化。的总目标是 这些研究是为了确定区分低级别和高级别的体细胞突变 胰腺的前驱病变。在对人体组织样本进行仔细的病理检查后，我们将 对患者匹配的低级别和高级别前体细胞进行下一代测序 无伴发浸润性癌。这些研究将使我们能够比较 这两种类型的前体和识别特定于高级别皮损的体细胞突变。按顺序 为了区分进展为高风险病变的驱动因素，我们将验证 这些突变是通过基因操作在创新的三维器官培养模型中实现的 人类胰腺肿瘤。综上所述，拟议的研究将有助于识别突变 导致胰腺高风险前驱病变的形成--这些变化 代表胰腺癌早期发现、治疗和预防的最佳靶点。

This proposal describes a research plan and training program to develop the principal investigator, Dr. Laura Wood, from junior faculty into an independent physician-scientist. Dr. Wood has performed seminal work in cancer genomics and has completed clinical training in Gastrointestinal, Liver, and Pancreatic Pathology. She was appointed Assistant Professor in July 2013, a tenure-track position with 75% protected time for the proposed studies. Her long-term goal is to develop an independent research program to characterize the molecular events that underlie multistep tumorigenesis in the pancreas. This program will leverage her existing expertise in genomics and pancreatic pathology; however, it will also require additional training in bioinformatics and cell biology in order to independently identify and functionally validate molecular events in pancreatic neoplasms. In order to realize these goals, Dr. Wood has assembled a diverse mentorship team with expertise in cancer genomics, pancreatic pathology, cell biology, and bioinformatics. Her career development plan includes formal coursework as well as seminars, lab meetings, and hands-on training. The proposed research and career development will guide Dr. Wood to a position leading a productive independent research group. Invasive pancreatic cancer arises from non-invasive precancerous lesions that are curable if detected early enough. These precursors include low-grade lesions (which have a low risk of malignant transformation) as well as high-grade lesions (which are equivalent to carcinoma in situ). Early detection of high-grade precursors before their transformation to carcinoma is the key to improving survival of patients with pancreatic neoplasms. In spite of the clinical importance, little is known about the alterations that distinguish low-grade and high-grade precursors in the pancreas. The overall goal of these studies is to determine the somatic mutations that distinguish low-grade from high-grade precursor lesions in the pancreas. After careful pathological review of human tissue samples, we will perform next generation sequencing on matched low-grade and high-grade precursors from patients without associated invasive carcinoma. These studies will allow us to compare the genetic alterations in both types of precursors and identify somatic mutations that are specific to high-grade lesions. In order to distinguish drivers of the progression to high-risk lesions, we will validate the functional effects of these mutations via genetic manipulation in an innovative three-dimensional organoid culture model of human pancreatic neoplasia. Taken together, the proposed studies will help to identify the mutations that causally contribute to the formation of high-risk precursor lesions in the pancreas – these changes represent the best targets for early detection, treatment, and prevention of pancreatic cancer.