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(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation

(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化

基本信息

批准号：
9922880
负责人：
SCOTT A WALDMAN
金额：
$ 35.69万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-09 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922880
关键词：
Address Adenomatous Polyposis Coli Alleles Automobile Driving Azoxymethane Binding Cancer Etiology Carcinogens Cell Nucleus Cells Cessation of life Chemoprevention Chromosomal Stability Chronic Colorectal Colorectal Cancer Colorectal Neoplasms Constipation Creativeness Data Development Disease Epithelial Epithelial Cells Epithelium Event Feedback Functional disorder Future Genetic Genetic Diseases Genetic Transcription Homeostasis Hormone replacement therapy Hormones Induced Mutation Intestines Knowledge Ligands Link Malignant Neoplasms Mediating Metabolic Molecular Mus Mutation Nuclear Oral Outcome Patients Property Regulation Role Signal Transduction Supplementation Testing Transgenic Organisms Translating Translations adenoma base beta catenin cancer chemoprevention colorectal cancer prevention design guanylin hormone deficiency innovation insight mouse model mutant mutant mouse model novel originality paracrine peptide hormone premalignant prevent programs public health relevance receptor reconstitution tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the 4th most common cancer and 2nd leading cause of cancer death. In >90% of sporadic cases, colorectal cancer initiates as mutations in APC (~85%) or its downstream degradation target, β-catenin (~5%). These mutations result in accumulation of β-catenin which translocates to the nucleus and regulates transcription driving epithelial dysfunction and formation of the premalignant field (adenomas). While a role for APC and β-catenin mutations in transformation is established, gaps in knowledge reflect an incomplete understanding of the pathophysiological events linking these mutations to formation of the premalignant field, the mechanisms mediating those events, and their reversibility as a basis for cancer chemoprevention. In that context, guanylin is a paracrine peptide hormone produced by epithelial cells in the colo-rectum. Guanylin binds to GUCY2C, a receptor which maintains epithelial homeostasis by regulating proliferation, chromosomal stability, and metabolic programming, in part, by preventing β-catenin accumulation. Recently, we revealed that guanylin loss silencing GUCY2C occurs in all colorectal tumors. Further, guanylin is lost in all adenomas, and in premalignant epithelia that precede adenoma formation. Unexpectedly, transgenic expression of guanylin (cannot be lost) in mice eliminated transformation induced by the carcinogen azoxymethane (AOM) which produces β-catenin mutations. Based on these observations, we propose testing the novel hypothesis that that there is a reciprocal feedback loop in which nuclear signaling by mutant APC-β-catenin induces guanylin loss required for transformation because guanylin-GUCY2C blocks β-catenin accumulation necessary for tumorigenesis. Here, the Pathophysiological Aim will test the hypothesis that guanylin loss silencing GUCY2C is required to form the premalignant field produced by mutant APC-β-catenin. These studies will demonstrate that eliminating guanylin in intestinal cells recapitulates the pathophysiology of transformation (guanylin loss mediates the disease). The Mechanistic Aim will test the hypothesis that mutant APC-β-catenin suppresses guanylin transcription because guanylin-GUCY2C blocks β-catenin accumulation required for transformation (this molecular mechanism mediates guanylin loss). These studies will shift the paradigm in colorectal cancer from a genetic disease of irreversible APC-β-catenin mutations to a disease of reversible guanylin insufficiency. The Chemoprevention Aim will test the hypothesis that transgenic guanylin replacement blocks β-catenin accumulation, epithelial dysfunction, and transformation induced by APC-β-catenin mutations (blocking guanylin loss prevents the disease). These studies will establish the chemoprevention paradigm that guanylin replacement eliminates intestinal transformation. In turn, these novel mechanistic insights will provide new opportunities for colorectal cancer prevention, including oral GUCY2C ligand supplementation. The potential for immediate translation is underscored by the approval of the oral GUCY2C ligand, linaclotide, to treat chronic constipation.

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prenatal Regeneration in Clinical Practice.

临床实践中的产前再生。

DOI：
10.1016/j.mayocp.2018.04.004
发表时间：
2018
期刊：
Mayo Clinic proceedings
影响因子：
8.9
作者：
Waldman,ScottA
通讯作者：
Waldman,ScottA

Cardiopoietic stem cell therapy in ischaemic heart failure: long-term clinical outcomes.

DOI：
10.1002/ehf2.13031
发表时间：
2020-12
期刊：
ESC heart failure
影响因子：
3.8
作者：
Bartunek J;Terzic A;Davison BA;Behfar A;Sanz-Ruiz R;Wojakowski W;Sherman W;Heyndrickx GR;Metra M;Filippatos GS;Waldman SA;Teerlink JR;Henry TD;Gersh BJ;Hajjar R;Tendera M;Senger S;Cotter G;Povsic TJ;Wijns W;CHART Program
通讯作者：
CHART Program

Enteroendocrine cell regulation of the gut-brain axis.

DOI：
10.3389/fnins.2023.1272955
发表时间：
2023
期刊：
FRONTIERS IN NEUROSCIENCE
影响因子：
4.3
作者：
Barton, Joshua R.;Londregan, Annie K.;Alexander, Tyler D.;Entezari, Ariana A.;Covarrubias, Manuel;Waldman, Scott A.
通讯作者：
Waldman, Scott A.