The role of stromal APC haploinsufficiency in colorectal tumorigenesis

基质 APC 单倍体不足在结直肠肿瘤发生中的作用

基本信息

批准号：
8703643
负责人：
James Peter Robinson
金额：
$ 10.18万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2014-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703643
关键词：
5q21 APC gene Adenomatous Polyposis Coli Adenomatous Polyps Alleles Anniversary Attenuated Award Basic Science Biology Cancerous Carcinoma Cell Line Cells Chemoprevention Chimera organism Clinical Colectomy Colon Colon Carcinoma Colonic Adenoma Colorectal Colorectal Adenoma Colorectal Cancer Commit Data Development Dissection Doctor of Philosophy Educational process of instructing Epidermal Growth Factor Epithelial Cells Foundations Funding Gastrointestinal Neoplasms Generations Germ-Line Mutation Goals Growth Growth Factor Health Hepatocyte Growth Factor Human Huntsman Cancer Institute at the University of Utah Immunohistochemistry Inflammation Inherited Institutes Interleukin-17 Intestinal Neoplasms Intestinal Polyposis Intestines Juvenile polyposis syndrome Laboratories Large Intestine Lasers Lead Loss of Heterozygosity MADH4 gene Malignant Neoplasms Manuscripts Measures Mentors Mus Mutation Nuclear Null Lymphocytes Peutz-Jeghers Syndrome Phase Play Polyps Population Population Growth Puberty Publications Reporter Research Research Personnel Research Training Reverse Transcriptase Polymerase Chain Reaction Role STK11 gene Serum Signal Transduction Stromal Cells Study models Syndrome Tamoxifen Testing Therapeutic Agents Time Training Training Programs Tumor Burden Uncertainty Universities Utah Visit adenoma anticancer research base cytokine design gastrointestinal improved intestinal epithelium loss of function meetings mouse model neoplastic novel therapeutics polyposis prevent prophylactic therapeutic target tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The candidate, James Robinson Ph.D. proposes a comprehensive five year research and training program within the Huntsman Cancer Institute part of the University of Utah. Familial Adenomatous Polyposis (FAP) is an inherited syndrome characterized by the development of hundreds of pre- cancerous polyps in the large intestine, some of which progress to cancers. Prophylactic colectomy is usually performed as a preventative measure. FAP is caused by germline mutations in the Adenomatous Polyposis Coli (APC) gene. APC mutations are also found in sporadic colorectal adenomas and 85% of colon cancers carry APC mutations. Consequently, FAP is an excellent model for the study of colon cancer because each adenoma represents an early step in tumorigenesis. Until recently it was widely accepted that APC mutations were alone sufficient for nuclear accumulation of ?-Catenin in intestinal epithelial cells and the onset of intestinal polyposis, but preliminary data suggests that additional growth signals or mutations are required. The candidate's hypothesis is that aberrant stromal cell signaling following loss or haploinsufficiency of APC drives tumorigenesis in adjacent predisposed epithelial cells. This project will expand the understanding of how stromal APC loss contributes to the development of neoplastic intestinal epithelium. The candidate's long-term research goals are to facilitate the development of new measures to prevent colonic adenoma formation by understanding the earliest cellular perturbations that follow APC mutation. If he can demonstrate that growth of early adenomas is driven by stromal signaling and identify which components of this signaling are potential therapeutic targets, completion of this project may radically improve measures to prevent and treat FAP and sporadic colon cancer. An accompanying research training program under the direction of Dr David Jones is a core component of the mentored (K99) period of the award, providing the candidate with a strong foundation in basic science, cancer research and the biology of colorectal cancer. This carefully developed research and training program will lead to: 1) important advances in the study of colorectal cancer, 2) the development of mouse models in which to test novel therapeutic agents, 3) the generation of data that will provide the basis for a highly competitive submission for R01 funding at the conclusion of the independent award (R00) period; and 4) transition of the candidate into an independent researcher.

描述（由申请人提供）：候选人 James Robinson 博士。提议在犹他大学亨斯曼癌症研究所内实施一项为期五年的综合研究和培训计划。家族性腺瘤性息肉病（FAP）是一种遗传综合征，其特征是大肠中出现数百个癌前息肉，其中一些进展为癌症。预防性结肠切除术通常作为预防措施进行。 FAP 是由腺瘤性结肠息肉病 (APC) 基因种系突变引起的。 APC 突变也见于散发性结直肠腺瘤，85% 的结肠癌携带 APC 突变。因此，FAP 是研究结肠癌的绝佳模型，因为每个腺瘤都代表肿瘤发生的早期步骤。直到最近，人们还普遍认为，仅 APC 突变就足以导致肠上皮细胞中 β-连环蛋白的核积累和肠息肉病的发生，但初步数据表明需要额外的生长信号或突变。候选人的假设是，APC 丢失或单倍体不足后的异常基质细胞信号传导会导致邻近易感上皮细胞发生肿瘤。该项目将加深对间质 APC 损失如何促进肿瘤性肠上皮的发展的理解。该候选人的长期研究目标是通过了解 APC 突变后最早的细胞扰动，促进开发新措施来预防结肠腺瘤形成。如果他能够证明早期腺瘤的生长是由基质信号传导驱动的，并确定该信号传导的哪些成分是潜在的治疗靶点，那么该项目的完成可能会从根本上改善预防和治疗 FAP 和散发性结肠癌的措施。 David Jones 博士指导下的配套研究培训计划是该奖项指导期 (K99) 的核心组成部分，为候选人提供基础科学、癌症研究和结直肠癌生物学方面的坚实基础。这项精心开发的研究和培训计划将带来：1）结直肠癌研究的重要进展，2）开发用于测试新型治疗药物的小鼠模型，3）生成数据，为研究提供基础。在独立奖励 (R00) 期结束时提交极具竞争力的 R01 资金申请； 4) 候选人转变为独立研究员。