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：
8965544
负责人：
James Peter Robinson
金额：
$ 24.9万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-27 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8965544
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 Adenoma Colorectal Cancer 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 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 abstracting adenoma anticancer research base beta catenin colon tumorigenesis 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

Abstract 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 β-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.

抽象的候选人詹姆斯·罗宾逊博士提出了为期五年的全面研究和培训。犹他大学亨茨曼癌症研究所的项目。息肉病 (FAP) 是一种遗传综合征，其特征是数百个先天性息肉病的发展大肠癌性息肉，其中一些进展为癌症。 FAP 是由种系突变引起的散发性结直肠腺瘤性息肉病 (APC) 基因也存在 APC 突变。经过测试，腺瘤和 85% 的结肠癌都携带 APC 突变，FAP 是一个优秀的模型。用于结肠癌的研究，因为每个腺瘤代表肿瘤发生的早期步骤。最近，人们普遍认为，仅 APC 突变就足以在细胞核中积累肠上皮细胞中的β-连环蛋白与肠息肉病的发病有关，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驱动肿瘤发生该项目将扩大对基质 APC 的了解。损失有助于肿瘤性肠上皮的长期发展。研究目标是促进制定预防结肠腺瘤的新措施如果可以的话，他可以通过了解 APC 突变后最早的细胞扰动来形成。证明早期腺瘤的生长是由基质信号传导驱动的，并确定哪些该信号传导的组成部分是潜在的治疗靶点，该项目的完成可能会从根本上改进预防和治疗 FAP 和散发性结肠癌的措施。 David Jones 博士指导下的培训计划是导师制 (K99) 的核心组成部分颁奖期间，为候选人提供基础科学、癌症方面的坚实基础这项精心制定的研究和培训计划。将导致：1）结直肠癌研究的重要进展，2）小鼠的发展测试新型治疗药物的模型，3）生成提供基础的数据在独立奖项 (R00) 结束时提交极具竞争力的 R01 资金申请期间；和 4) 候选人转变为独立研究员。