The Impact of Gut Microbiota on the Sex Difference in Bladder Cancer

肠道菌群对膀胱癌性别差异的影响

• 批准号: 10323683
• 负责人: Xue Sean Li
• 金额: $ 19.13万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-04 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323683
• 关键词: Address; Age; Androgen Metabolism; Androgens; Antibiotics; Biological; Biology; Bladder; Bladder Neoplasm; Cancer Biology; Cancer Patient; Cells; Coupled; Critiques; Epigenetic Process; Estrogens; Feedback; Female; Four Core Genotypes; Funding Opportunities; Genitourinary system; Genomic approach; Geography; Goals; Gonadal Steroid Hormones; Grant; Health Care Costs; Hormone use; House mice; Human body; Incidence; Individual; Knowledge; Light; Male Castration; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Microbe; Mus; Nature; Outcome; Phenotype; Play; Recurrence; Reporting; Research; Role; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; Testing; Testosterone; Time; Variant; Woman; X Chromosome; cancer health disparity; cancer initiation; cancer risk; cancer therapy; cancer type; checkpoint inhibition; chemical carcinogen; commensal microbes; design; fecal transplantation; gender disparity; genetic approach; germ free condition; gut microbes; gut microbiota; improved; innovation; insight; male; men; microbial; microbial community; microbiome; microbiota; microorganism; mortality; response; sex; sex disparity; socioeconomics; trend; tumor; tumor growth

Men are 3-5 times more likely than women to develop and die from bladder cancer (BCa) but the underlying mechanisms of these gender disparities in BCa are poorly understood. This is highlighted as the major knowledge gaps in the Funding Opportunity Announcement (FOA) “Biology of Bladder Cancer (PAR-19-184)”: 1) “identifying biological mechanisms underlying disparities in sex in bladder cancer incidence”; and 2) “investigating the role of the microbiome in the bladder cancer biology”. The lack of understanding is due in part to the fact that the sex-biasing factors are often confounding co-variants. For example, the sex chromosomes are coupled with the sex hormones. Because of the confounding nature, the impacts of individual sex-biasing factors are exceedingly difficult to quantify. Gut microbiota differs significantly between sexes. Its potential sex- specific role in BCa remains unknown despite a preponderance of evidence that gut microbiota exerts the profound effects on cancer initiation, progression and therapy. To gain insight onto the sex differences in BCa, we will test the hypothesis that the gut microbiota plays a sex-specific role in regulating BCa incidence and mortality. To test this hypothesis, we have designed two specific aims using the innovative genetic and genomic strategies. First, we will determine whether the eradication of microbiota blunts the sex differences in BCa incidence and mortality; And second, we will identify gut microorganisms that are closely associated with BCa incidence and mortality. Upon conclusion, the proposal is expected to significantly advance our knowledge of the gender disparities in cancer and to identify candidate gut microbes that are tightly associated with BCa incidence and mortality.

男性患膀胱癌和死于膀胱癌的可能性是女性的3-5倍，但潜在的 BCA中这些性别差异的机制还知之甚少。这被突出显示为主要的 资助机会公告(FOA)“膀胱癌生物学(PAR-19-184)”中的知识差距： 1)“找出膀胱癌发病率性别差异的生物学机制”；及2) 《研究微生物群在膀胱癌生物学中的作用》。缺乏理解是部分原因。 事实上，性别偏见因素往往是令人困惑的协变量。例如，性染色体 与性激素结合在一起。由于混杂的性质，个体性别偏见的影响 这些因素非常难以量化。肠道微生物区系在不同性别之间存在显著差异。它潜在的性行为- 尽管有大量证据表明肠道微生物区系在BCA中发挥作用，但BCA中的具体作用仍不清楚 对癌症的发生、发展和治疗产生深远的影响。为了深入了解BCA的性别差异， 我们将检验这样一个假设，即肠道微生物区系在调节BCA发病率和 死亡率。为了验证这一假设，我们设计了两个特定的目标，使用创新的遗传和基因组 战略。首先，我们将确定根除微生物区系是否会削弱BCA的性别差异 发病率和死亡率；第二，我们将确定与BCA密切相关的肠道微生物 发病率和死亡率。在结论中，这项建议有望大大提高我们对 癌症中的性别差异，并确定与BCA密切相关的候选肠道微生物 发病率和死亡率。