The Hedgehog Pathway and Pancreatic Neoplasia

描述（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因子Sonic hedgehog在胰腺肿瘤发生中的作用。职业发展计划侧重于获得胰腺癌/病理和发展的基本知识和实验技能。Drs。导师Andrew Warshaw，因胰腺癌研究而享誉国际，共同导师Drucilla Roberts， GI发展和hedgehog信号的独立研究者，已经承诺他们的专业知识和资源来指导她的项目。由胰腺发育生物学家Douglas Melton博士和胰腺/胃肠道病理学家Gregory Lauwers博士组成的非正式咨询委员会将加强候选人在小鼠模型和胰腺发育和病理学方面的培训。麻省总医院和哈佛医学院的联合资源为这位年轻研究者的发展提供了丰富的研究环境。Hedgehog （Hh）信号是胚胎胰腺发育的重要途径，其调控不当与多种癌症有关，也可能是人类胰腺癌的重要介质。SHH在胰腺癌及其前体病变胰腺上皮内瘤变（PanlN）中异常表达。Shh在胰腺内胚层错误表达的小鼠胰腺会出现异常的管状结构，这是人类pann -1和-2的表型。此外，Hedgehog信号在原发性和转移性胰腺腺癌细胞系中仍然活跃，并且在体外和体内抑制Hh信号可诱导细胞凋亡并阻断增殖。因此，Hh通路可能在胰腺癌的发生和维持中都很重要。候选人提出的目标是：1)建立Tet条件小鼠模型，以确定成人胰腺中Shh的错误表达是否足以导致胰腺肿瘤；2)通过实时荧光定量PCR检测Shh及其通路成员在人类肿瘤中的表达情况；3)确定HH通路失活是否会影响使用新鲜外科移植体的小鼠异种移植模型中胰腺癌的生物学行为。这将使我们更好地了解这一途径在人类胰腺癌中的作用，从而可以利用它来开发新的诊断和治疗方式。

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.