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）表现出惊人的性偏见：男性的发展和死亡的可能性是女性的3-5倍来自BCA。即使在已知的危险因素（例如吸烟，感染，职业危害，文化和这种现象持续存在校正环境因素。尽管经历了长期的临床观察由于缺乏机械理解，男人和女人仍然接受相对相似的治疗方法基于生物学的有用治疗方法。在此提案中，我们寻求阐明性的机械基础肿瘤生物学中的双态性。众所周知，性腺激素作用（GHE），由性腺 - 驱动BCA性别差异的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，我们报告了意外的性染色体效应（SCE）独立地促进了BCA的性二态性；我们发现SCE主要由赖氨酸（K）脱甲基酶6a（KDM6A），它在膀胱中充当雌性偏见的肿瘤抑制基因。 KDM6A脱甲基酶是一种多功能表观遗传调节剂，可控制两种酶促中的组蛋白甲基化活动发展和独立机制。我们将特定的表观基因组称为性别表观基因组。我们假设由KDM6A直接和AR编程的性表观组对控制基因表达和BCA中的性二态性。我们设计了三个特定目的来检验这一假设：1）确定KDM6A是否直接形成性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是否反对依赖KDM6A的性别基因组膀胱; 3）确定性别基因组是否在膀胱期间差异调节基因致癌作用。该提案的成功将催化性别偏见基因和调节性的识别设计性别特异性BCA筛查和治疗的元素。我们提出的研究的结果将还提高了男性更大BCA发生的机理理解，并带领未来的努力根据患者的生物学性别预防和治疗BCA。因为男性在癌症发生率和在大多数非生殖癌症类型中观察到死亡率，对性的理解得到了改善 BCA中的二态性也将对这些癌症产生广泛的影响。