The Molecular Basis of Juvenile Polyposis
幼年性息肉病的分子基础
基本信息
- 批准号:6765989
- 负责人:
- 金额:$ 26.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:bone morphogenetic proteinscarcinogenesisclinical researchcolorectal neoplasmsfamily geneticsgastrointestinal neoplasmsgene mutationgenetic screeninggenetic susceptibilitygenetic transcriptionhuman genetic material taghuman subjectlinkage mappingmolecular oncologyneoplastic transformationpatient oriented researchpreneoplastic statetransforming growth factors
项目摘要
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(由申请人提供):幼年性息肉病(JP)是一种错构瘤性胃肠道息肉综合征,患者有很大的风险发展为结直肠癌。我们以前已经证明JP是由Smad4和BMPR1A的胚系突变引起的,这暗示了骨形态发生和转化生长因子-β超家族信号通路在JP相关肿瘤发生中的作用。显微镜下,幼年性息肉有明显扩张的固有层,有丰富的间质,炎性浸润物和正常的覆盖上皮。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、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胃肠道幼年息肉是如何引发癌症的。这项应用的目的是确定与青少年息肉形成有关的分子遗传事件。中心假设是转化生长因子-β超家族基因的胚系突变使患者易患JP,胃肠道息肉的发生是这些和相关信号通路进一步改变的结果。我们建议通过两个特定的目标来实现我们的目标:1)通过遗传连锁和位置候选方法发现新的JP基因;2)检测幼年性息肉转录本中的整体基因表达模式,以确定参与其形成的共同遗传途径,以及息肉中不同细胞类型对这些表达模式的特殊贡献。总而言之,这些研究将确定JP患者发生的分子遗传变化,从出生时的胚系突变开始,经过胃肠道的体细胞变化,导致幼年性息肉。一个新的JP基因的发现将进一步确定特定的转化生长因子-β超家族通路,其信号改变导致这种表型,基因表达研究将描绘导致幼年性息肉的次要事件,以及那些其转录受到种系突变影响的基因。从这个项目中获得的见解将为未来的研究奠定基础,以确定幼年息肉转化为癌症所需的特定遗传事件,并研究这一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进症状前基因测试,以及确定JP息肉消退和癌症预防的新治疗靶点,使JP患者受益。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES R HOWE其他文献
JAMES R HOWE的其他文献
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{{ truncateString('JAMES R HOWE', 18)}}的其他基金
Project 3: A Genomic Approach to Improved Diagnosis and Treatment of Neuroendocrine Tumors
项目 3:改进神经内分泌肿瘤诊断和治疗的基因组方法
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8850627 - 财政年份:2015
- 资助金额:
$ 26.26万 - 项目类别:
Project 3: A Genomic Approach to Improved Diagnosis and Treatment of Neuroendocrine Tumors
项目 3:改进神经内分泌肿瘤诊断和治疗的基因组方法
- 批准号:
10264530 - 财政年份:2015
- 资助金额:
$ 26.26万 - 项目类别:
Regulation of SMAD4 and BMPR1A Expression in Juvenile Polyposis
SMAD4 和 BMPR1A 在幼年性息肉病中表达的调控
- 批准号:
7568021 - 财政年份:2009
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
7737350 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
8440994 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
7342787 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
7192052 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
7869478 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
Single Channel Properties and Structure of Glutamate Receptors
谷氨酸受体的单通道特性和结构
- 批准号:
7536090 - 财政年份:2007
- 资助金额:
$ 26.26万 - 项目类别:
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