Molecular Basis of Juvenile Polyposis

幼年性息肉病的分子基础

• 批准号: 6684471
• 负责人: JAMES R HOWE
• 金额: $ 26.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684471
• 关键词: bone morphogenetic proteins; carcinogenesis; clinical research; colorectal neoplasms; family genetics; gastrointestinal neoplasms; gene mutation; genetic screening; genetic susceptibility; genetic transcription; human genetic material tag; human subject; linkage mapping; molecular oncology; neoplastic transformation; patient oriented research; preneoplastic state; transforming growth factors

DESCRIPTION (provided by applicant): Juvenile Polyposis (JP) is a hamartomatous gastrointestinal polyposis syndrome in which affected patients are at significant risk for developing colorectal cancer. We have previously shown that JP is caused by germline mutations of SMAD4 and BMPR1A, implicating the bone morphogenetic and TGF-beta superfamily signaling pathways in JP-associated tumorigenesis. Microscopically, juvenile polyps have a markedly expanded lamina propria, with abundant stroma, an inflammatory infiltrate, and normal overlying epithelium. However, Jp-associated cancers are epithelial, and the process by which these polyps develop and how they transform to adenocarcinoma represents a unique and largely unexplored mechanism of carcinogenesis. The long-term goal of these studies is to define how cancers arise from juvenile polyps of the gastrointestinal tract. The objective of this application is to determine the molecular genetic events involved in juvenile polyp formation. The central hypothesis is that germline mutations in TGF-beta superfamily genes predispose patients to JP, and gastrointestinal polyps develop as a consequence of further alterations in these and related signaling pathways. We propose to achieve our objective through two Specific Aims: 1) To discover new JP genes by genetic linkage and positional candidate approaches; and 2) To examine patterns of global gene expression in the transcriptomes of juvenile polyps in order to define the common genetic pathways involved in their formation, and the specific contributions of different cell types within polyps to these expression patterns. Collectively, these studies will define the molecular genetic changes occurring in JP patients, beginning at birth with germline mutations and progressing through somatic alterations in the gastrointestinal tract, leading to juvenile polyps. Identification of a new JP gene will further define the specific TGF-beta superfamily pathways whose altered signaling brings about this phenotype, and gene expression studies will delineate the secondary events leading to juvenile polyps, and those genes whose transcription is affected by the germline mutations. The insights gained from this project will lay the groundwork for future studies to determine the specific genetic events required for the transformation of juvenile polyps into cancers, and to study the contribution of this novel mechanism of carcinogenesis in sporadic colorectal tumors. These studies will also benefit JP patients by improving presymptomatic genetic testing, and identification of new therapeutic targets for polyp regression and cancer prevention in JP.

描述（由申请方提供）：幼年性息肉病（JP）是一种错构瘤性胃肠道息肉综合征，受影响的患者具有发生结直肠癌的显著风险。我们以前已经证明，JP是由SMAD 4和BMPR 1A的种系突变引起的，暗示了骨形态发生和TGF-β超家族信号通路与JP相关的肿瘤发生有关。显微镜下，幼年息肉的固有层明显扩张，有丰富的基质、炎症浸润和正常的上覆上皮。然而，Jp相关的癌症是上皮性的，这些息肉的发展过程以及它们如何转化为腺癌代表了一种独特的且在很大程度上未被探索的致癌机制。这些研究的长期目标是确定癌症是如何从青少年胃肠道息肉中产生的。本申请的目的是确定参与幼年息肉形成的分子遗传事件。核心假设是TGF-β超家族基因的种系突变使患者易患JP，并且胃肠道息肉的发展是这些和相关信号通路进一步改变的结果。我们建议通过两个具体目标实现我们的目标：1）通过遗传连锁和位置候选方法发现新的JP基因; 2）检查幼年息肉转录组中的全局基因表达模式，以确定参与其形成的共同遗传途径，以及息肉内不同细胞类型对这些表达模式的具体贡献。总的来说，这些研究将确定JP患者中发生的分子遗传变化，从出生时的生殖系突变开始，通过胃肠道的体细胞改变进展，导致青少年息肉。新的JP基因的鉴定将进一步确定特定的TGF-β超家族通路，其改变的信号传导导致这种表型，基因表达研究将描述导致幼年息肉的继发事件，以及那些转录受种系突变影响的基因。从该项目中获得的见解将为未来的研究奠定基础，以确定青少年息肉转化为癌症所需的特定遗传事件，并研究这种新的致癌机制在散发性结直肠肿瘤中的作用。这些研究还将通过改善症状前基因检测和确定新的治疗靶点来使JP患者受益，用于JP中的息肉消退和癌症预防。