The Hedgehog Pathway and Pancreatic Neoplasia

申请人描述(申请人提供)：申请人是一名普通外科医生，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/病理学和发展方面的基本知识和实验技能。Mentor博士安德鲁·沃肖博士以其在胰腺癌方面的工作而闻名国际，而联合Mentor博士Dr.Drucilla Roberts则是一位在胃肠道发育和刺猬信号方面颇有成就的独立研究员，他们投入了他们的专业知识和资源来指导她的项目。一个由胰腺发育生物学家道格拉斯·梅尔顿博士和胰腺/胃肠道病理学家格雷戈里·劳尔斯博士组成的非正式咨询委员会将加强候选人在小鼠建模、胰腺发育和病理学方面的培训。马萨诸塞州总医院和哈佛医学院的联合资源为这位年轻的研究员的发展提供了丰富的研究环境。Hedgehog(HH)信号通路是胚胎胰腺发育过程中的一条重要途径，其调控不当与多种癌症的发生密切相关，也可能是人类胰腺癌的重要调节因子。ShH在胰腺癌及其癌前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PanlN-1和PanlN-2的表型。此外，Hedgehog信号在原发癌和转移性胰腺癌的细胞系中仍然活跃，抑制HH信号在体外和体内都诱导细胞凋亡和抑制增殖。因此，HH通路可能在胰腺癌的发生和维持中起重要作用。候选人提出的目标是：1)建立TET条件性小鼠模型，以确定Shh在成人胰腺中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确定Shh及其通路成员在人类癌症中的表达情况；以及3)利用新鲜的外科外植体，确定HH通路的失活是否会影响小鼠胰腺癌的生物学行为。这将使我们更好地了解该通路在人类胰腺癌中的作用，以便将其用于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.