The Hedgehog Pathway and Pancreatic Neoplasia

Hedgehog通路和胰腺肿瘤

• 批准号: 6812673
• 负责人: SARAH P THAYER
• 金额: $ 13.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-10 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812673
• 关键词: animal genetic material tag; biological signal transduction; carcinogenesis; cell growth regulation; clinical research; disease /disorder etiology; disease /disorder model; gene expression; gene induction /repression; gene mutation; genetically modified animals; human tissue; immunocytochemistry; laboratory mouse; model design /development; neoplasm /cancer genetics; pancreas neoplasms; polymerase chain reaction; tissue /cell culture

DESCRIPTION (provided by applicant): The applicant is a general surgeon whose clinical and research focus is pancreatic cancer. She plans to study the role of the developmental signaling factor Sonic hedgehog in pancreatic tumorigenesis. The career development plan focuses on acquiring basic knowledge and experimental skills in pancreatic cancer/pathology and development. Drs. Andrew Warshaw, mentor, internationally known for his work in pancreatic cancer, and Drucilla Roberts, co-mentor, an accomplished independent investigator in GI development and hedgehog signaling, have committed their expertise and resources to guiding her program. An informal advisory committee, consisting of the pancreatic developmental biologist Dr. Douglas Melton and pancreatic/ GI pathologist Dr. Gregory Lauwers, will augment the candidate's training in mouse modeling and pancreatic development and pathology. The combined resources of the Massachusetts General Hospital and Harvard Medical School provide a rich research environment for this young investigator's development. Hedgehog (Hh) signaling, an essential pathway during embryonic pancreatic development whose misregulation has been implicated in several forms of cancer, may also be an important mediator in human pancreatic carcinoma. SHH is abnormally expressed in pancreatic cancer and its precursor lesions, pancreatic intra-epithelial neoplasia (PanlN). Pancreata of mice in which Shh is misexpressed in the pancreatic endoderm develop abnormal tubular structures, a phenocopy of human PanlN-1 and -2. Furthermore, Hedgehog signaling remains active in cell lines from primary and metastatic pancreatic adenocarcinomas, and inhibition of Hh signaling induces apoptosis and blocks proliferation both in vitro and in vivo. Thus, the Hh pathway may be important in both initiation and maintenance of pancreatic cancer. The candidate's proposed aims are: 1) to develop a Tet conditional mouse model to determine whether misexpression of Shh in the adult pancreas is sufficient to cause pancreatic neoplasia; 2) to determine the prevalence of expression of Shh and pathway members in human cancer by real-time PCR; and 3) to determine whether inactivation of the HH pathway can influence the biologic behavior of pancreatic cancer in a murine xenograft model using fresh surgical explants. This will allow us to better understand the role of this pathway in human pancreatic cancer, so that it may be exploited for new diagnostic and therapeutic modalities.

描述（由申请人提供）：申请人是一名普通外科医生，其临床和研究重点是胰腺癌。她计划研究发育信号传导因子声音刺猬在胰腺肿瘤发生中的作用。职业发展计划的重点是获取胰腺癌/病理学和发育中的基本知识和实验技能。博士。导师安德鲁·沃肖（Andrew Warshaw）以胰腺癌的工作而闻名，而在GI开发和刺猬信号方面有成就的独立研究员Drucilla Roberts则承诺了他们的专业知识和资源来指导她的计划。由胰腺发展生物学家道格拉斯·梅尔顿（Douglas Melton）和胰腺/胃肠道病理学家格雷戈里·劳沃斯（Gregory Lauwers）博士组成的非正式咨询委员会将增加候选人在老鼠建模和胰腺发展和病理学方面的培训。马萨诸塞州综合医院和哈佛医学院的综合资源为这位年轻研究者的发展提供了丰富的研究环境。刺猬（HH）信号传导是胚胎胰腺发育过程中的一种基本途径，其危机与几种形式的癌症有关，也可能是人类胰腺癌的重要介体。 SHH在胰腺癌及其前体病变，胰腺上皮内肿瘤（PANLN）中异常表达。在胰腺内胚层中SHH被misexplated的小鼠的胰腺形成异常的管状结构，这是人类panln -1和-2的表观。此外，刺猬信号在来自原发性和转移性胰腺腺癌的细胞系中保持活跃，HH信号传导的抑制会诱导凋亡，并在体外和体内阻止增殖。因此，HH途径在胰腺癌的启动和维持中都可能很重要。候选人提出的目的是：1）开发有条件的小鼠模型，以确定成年胰腺中SHH的表现是否足以引起胰腺肿瘤； 2）通过实时PCR确定人类癌症中SHH和途径成员表达的流行； 3）为了确定使用新鲜手术外植体在鼠异种移植模型中，HH途径的失活是否可以影响胰腺癌的生物学行为。这将使我们能够更好地理解该途径在人类胰腺癌中的作用，从而可以利用它用于新的诊断和治疗方式。