The Hedgehog Pathway and Pancreatic Neoplasia

Hedgehog通路和胰腺肿瘤

• 批准号: 7273561
• 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/7273561
• 关键词: Adult; Advisory Committees; Apoptosis; Behavior; Cell Line; Clinical Research; Commit; Development; Development Plans; Embryo; Endoderm; Environment; Epithelial; Erinaceidae; General Hospitals; Growth; Human; In Vitro; Knowledge; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Massachusetts; Mediator of activation protein; Mentors; Metaplasia; Metastatic Pancreatic Adenocarcinoma; Modality; Mus; Neoplasms; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic carcinoma; Pathologist; Pathology; Pathway interactions; Phenocopy; Play; Polymerase Chain Reaction; Prevalence; Research; Research Personnel; Resources; Role; SHH gene; Signal Pathway; Signal Transduction; Structure; Surgeon; Tetanus Helper Peptide; Tetracycline; Tetracyclines; Therapeutic; Time; Training; Tubular formation; Work; Xenograft Model; career; gastrointestinal; in vivo; malignant phenotype; medical schools; member; mouse model; novel diagnostics; pancreatic neoplasm; pancreatic tumorigenesis; programs; skills; smoothened signaling pathway

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因子Sonic hedgehog在胰腺肿瘤发生中的作用。职业发展计划的重点是获得胰腺癌/病理学和发展的基本知识和实验技能。Andrew Warshaw博士，导师，以他在胰腺癌方面的工作而闻名，Drucilla Roberts，共同导师，一位在GI发育和刺猬信号方面有成就的独立研究者，致力于他们的专业知识和资源来指导她的计划。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和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综合资源为这位年轻的研究者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通路，其调控异常与多种癌症有关，也可能是胰腺癌的重要介导因子。SHH在胰腺癌及其前驱病变胰腺上皮内瘤变（PanIN）中异常表达。其中Shh在胰腺内胚层中错误表达的小鼠的胰腺发育异常的管状结构，这是人PanIN-1和PanIN-2的表型。此外，Hedgehog信号传导在来自原发性和转移性胰腺腺癌的细胞系中保持活性，并且Hh信号传导的抑制在体外和体内诱导细胞凋亡并阻断增殖。因此，Hh通路在胰腺癌的发生和维持中可能是重要的。候选人提出的目标是：1）开发泰特条件性小鼠模型，以确定成年胰腺中Shh的错误表达是否足以导致胰腺肿瘤; 2）通过实时PCR确定Shh和途径成员在人类癌症中的表达流行率;和3）确定HH途径的失活是否可以影响使用新鲜外科外植体的鼠异种移植模型中胰腺癌的生物学行为。这将使我们能够更好地了解这一途径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。