Sexual Dimorphism in Bladder Cancer

膀胱癌的性别二态性

基本信息

批准号：
10522918
负责人：
Xue Sean Li
金额：
$ 57.72万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-02 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522918
关键词：
Address Affect Androgen Receptor Bacterial Artificial Chromosomes Biological Biological Availability Biology Bladder Bladder Neoplasm Chemicals Chromatin Clinical Data Development Disease Down-Regulation Environmental Risk Factor Epigenetic Process Exhibits Female Four Core Genotypes Future Gene Expression Gene Expression Regulation Gene Family Gene Targeting Genes Genitourinary system Glucuronosyltransferase Gonadal Hormones Gonadal Steroid Hormones Gonadal structure Histones Hormonal Human Incidence Infection Investigation Knockout Mice Lead Libido Light Link Lysine Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Mediating Modeling Mus Mutation Oncogenes Outcome Ovary Pathway interactions Patients Physiological Regulation Regulatory Element Reporting Risk Factors Role Screening for cancer Sex Bias Sex Chromosomes Sex Differences Shapes Smoking System Technology Testing Testis Time Transgenic Mice Tumor Biology Tumor Suppressor Genes Tumor Suppressor Proteins UGT1A1 gene Uridine Urothelium Woman X Chromosome XX male XY females base biological sex cancer type carcinogenesis conditional knockout design epigenome gain of function histone methylation improved in vivo male men mortality mutant novel occupational hazard prevent programs sex sex disparity sexual dimorphism success transcription factor transcriptome tumor tumorigenesis

项目摘要

Bladder cancer (BCa) exhibits a striking sex bias: men are 3-5 times more likely than women to develop and die from BCa. Even when known risk factors such as smoking, infection, occupational hazards, cultural and environmental factors are corrected for, this phenomenon persists. Despite this long-standing clinical observation, men and women still receive relatively similar treatments due to a lack of mechanistic understanding to derive useful treatments based on biological sex. In this proposal, we seek to elucidate the mechanistic basis of sexual dimorphism in tumor biology. It is well established that gonadal hormone effects (GHE), defined by gonad- derived hormonal factors that drive sex disparities in BCa, are primarily mediated by male dominant androgens and androgen receptor (AR). Recently, we reported an unexpected sex chromosome effect (SCE) that independently contributes to the sexual dimorphism of BCa; we found that SCE is predominantly mediated by lysine (K) demethylase 6a (KDM6A), which functions as a female-biased tumor suppressor gene in the bladder. KDM6A demethylase is a versatile epigenetic regulator that controls histone methylations in both enzymatic activity development and independent mechanisms. We will refer the sex-specific epigenome to as the sex epigenome. We hypothesize that the sex epigenome, programed by KDM6A directly and AR indirectly, controls sexual dimorphism in gene expression and BCa. We designed three specific aims to test this hypothesis: 1) to determine whether KDM6A shapes directly the sex epigenome and regulates the local bioavailability of sex hormones in the bladder; 2) to determine whether AR opposes the KDM6A-dependent sex epigenome in the bladder; and 3) to determine whether the sex epigenome differentially regulates genes during bladder carcinogenesis. Success of the proposal will catalyze the identification of sex-biased genes and regulatory elements for the design of sex-specific BCa screening and treatment. Results from our proposed studies will also advance the mechanistic understanding behind greater BCa incidence in males and lead future efforts to prevent and treat BCa according to a patient's biological sex. Because male dominance in cancer incidence and mortality is observed across most non-reproductive cancer types, an improved understanding of sexual dimorphism in BCa will also have widespread implications on these cancers.

膀胱癌 (BCa) 表现出显着的性别偏见：男性发生和死亡的可能性是女性的 3-5 倍来自BC省。即使存在已知的风险因素，如吸烟、感染、职业危害、文化和环境因素得到纠正后，这种现象仍然存在。尽管经过长期的临床观察，由于缺乏机制理解，男性和女性仍然接受相对相似的治疗基于生物性别的有用治疗。在本提案中，我们试图阐明性行为的机制基础肿瘤生物学中的二态性。众所周知，性腺激素效应（GHE）由性腺定义驱动 BCA 性别差异的衍生激素因素主要由男性主导雄激素介导和雄激素受体（AR）。最近，我们报告了一种意想不到的性染色体效应（SCE）独立地促成 BCa 的性别二态性；我们发现 SCE 主要由赖氨酸 (K) 去甲基化酶 6a (KDM6A)，在膀胱中充当女性偏向的肿瘤抑制基因。 KDM6A 去甲基化酶是一种多功能表观遗传调节因子，可控制组蛋白甲基化活动发展和独立机制。我们将性别特异性表观基因组称为性别表观基因组。我们假设由 KDM6A 直接编程和 AR 间接编程的性别表观基因组控制基因表达和 BCa 的性别二态性。我们设计了三个具体目标来检验这一假设：1）确定 KDM6A 是否直接塑造性别表观基因组并调节性别的局部生物利用度膀胱中的激素； 2) 确定 AR 是否与 KDM6A 依赖性性别表观基因组相反膀胱; 3) 确定性别表观基因组是否在膀胱发育过程中差异调节基因致癌作用。该提案的成功将促进性别偏见基因的识别和监管性别特异性 BCa 筛查和治疗设计的要素。我们提议的研究结果将还促进了对男性 BCA 发病率较高背后的机制的理解，并引导未来的努力根据患者的生物性别预防和治疗BCa。因为男性在癌症发病率中占主导地位在大多数非生殖癌症类型中都观察到死亡率，提高了对性的了解 BCa 的二态性也将对这些癌症产生广泛的影响。