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.

抽象的膀胱癌是男性第四大癌症，女性是第11位。尽管有那个剑术发展和功能不是性马依赖性的，男人的发展可能性要高三倍膀胱癌比女性。吸烟已被证明不是这种性别偏见的贡献者。反而，内在的性别差异可能是男性对膀胱癌敏感性的分子机制。性激素和性染色体是显而易见的嫌疑人膀胱癌。实际上，啮齿动物中的实验证据强烈支持雄激素的关键作用在化学诱导的膀胱癌模型中促进癌症发展的受体。此外雄激素信号传导，另一个不可否认的强大的尿路发育和癌变是Wnt信号通路。 β-catenin是规范Wnt信号的信号积分器 AR和β-catenin物理相互作用与协同激活转录。这种相互作用至关重要在生殖器男性化，膀胱癌发展和进展。尽管这两种途径在膀胱致癌中起着至关重要的作用，但它们的直接可能是膀胱癌倡议的驱动因素的转录目标仍然难以捉摸。在这个应用程序，我们建议使用最近开发的功能强大的技术，分开Damid来揭示体内在膀胱癌发展过程中，AR，P300和β-catenin的下游转录靶标。目标 1，我们将使用新生成的转基因模型揭示直接AR和P300转录目标致癌物诱导的膀胱癌模型。接下来，在AIM 2中，我们将在膀胱类骨骼上使用spdamid到揭示AR和β-catenin的直接靶标，然后是siRNA功能屏幕，以促进其作用器官形成。这些研究总之大大提高了我们对膀胱癌的理解启动，尤其是由AR和WNT信号控制的启动。