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Androgen and Wnt signaling in bladder cancer

膀胱癌中的雄激素和 Wnt 信号传导

基本信息

批准号：
10727745
负责人：
Liang Ma
金额：
$ 21.37万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727745
关键词：
Address Adenine Adult Androgen Receptor Androgens Bacterial DNA Binding Proteins Biological Biological Assay Bladder Bladder Neoplasm Cancer Model Carcinogens Cell Proliferation Chemicals Chimeric Proteins Complex DNA DNA-Binding Proteins Development EP300 gene Embryo Enzymes Epithelium Gene Expression Genes Genetic Transcription Genital Genitalia Genitourinary system Gonadal Steroid Hormones Incidence Knowledge Laboratories Lower urinary tract Malignant Neoplasms Malignant neoplasm of urinary bladder Mammalian Cell Maps Masculine Methylation Modeling Molecular Organoids Pathway interactions Physiological Play Predisposition Proteins Protocols documentation Publications Publishing Recording of previous events Reporting Research Rodent Role Sex Bias Sex Chromosomes Sex Differences Signal Transduction Site-Specific DNA-Methyltransferase (Adenine-Specific)Small Interfering RNA Smoking Technology Testing Transgenic Mice Transgenic Model Transgenic Organisms Urothelium WNT Signaling Pathway Woman beta catenin cancer initiation carcinogenesis clinically relevant improved in vivo male men protein complex reconstitution sex tool transcription factor transcriptome sequencing

项目摘要

ABSTRACT Bladder cancer is the 4th most common cancer in men and 11th in women. Despite that bladder development and function are not sex hormone-dependent, men are three times more likely to develop bladder cancer than women. Smoking has been shown not to be a contributor for this gender bias. Instead, intrinsic sex-differences likely underpin the molecular mechanism for male susceptibility to bladder cancer. Sex hormones and sex chromosomes are obvious suspects to account for this male predilection for bladder cancer. In fact, experimental evidence in rodents strongly support a crucial role for androgen receptor in promoting cancer development in a chemical-induced bladder cancer model. In addition to androgen signaling, the other undeniably powerful regulator of lower urinary tract development and carcinogenesis is the WNT signaling pathway. β-catenin is the signal integrator of canonical WNT signaling and AR and β-catenin physically interact to synergistically activate transcription. This interaction is crucial for downstream target expression during genital masculinization, bladder cancer development and progression. Despite the crucial roles these two pathways play in bladder carcinogenesis, their direct transcriptional targets, which are likely drivers of bladder cancer initiation, remain elusive. In this application, we propose to use a recently developed powerful technology, Split DamID to reveal in vivo transcriptional targets downstream of AR, p300 and β-catenin during bladder cancer development. In Aim 1, we will use our newly generated transgenic model to reveal direct AR and p300 transcriptional targets in a carcinogen-induced bladder cancer model. Next, in Aim 2, we will use SpDamID on bladder organoids to reveal AR and β-catenin direct targets, followed by siRNA functional screen for their roles in promoting organoid formation. Together, these studies should greatly improve our understanding of bladder cancer initiation, especially those controlled by AR and Wnt signaling.

摘要