Sex, Chromosomes, and Immunity in Bladder Cancer

膀胱癌中的性别、染色体和免疫

• 批准号: 10629077
• 负责人: Xue Sean Li
• 金额: $ 227.23万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629077
• 关键词: Affect; Anatomy; Androgen Receptor; Androgens; Applications Grants; Automobile Driving; B-Lymphocytes; Benchmarking; Biological; Biology; Bladder; Bladder Neoplasm; CD8-Positive T-Lymphocytes; Cancer Biology; Cancer Center; Cancer Patient; Chromosomes; Clinical; Clinical Management; Collaborations; Communication; Comprehensive Cancer Center; Consultations; Data; Data Science Core; Development; Disease; Doctor of Philosophy; Environmental Risk Factor; Epigenetic Process; Estrogens; Experimental Designs; Female; Foundations; Gene Targeting; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Growth; Hormonal; Image Analysis; Immunity; Immunocompetent; Immunologic Monitoring; Immunologics; Immunology; Incidence; Infection; Institution; Joints; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Medical Oncology; Medical center; Medicine; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Ohio; Paper; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Play; Prevalence; Program Research Project Grants; Publications; Publishing; Receptor Signaling; Recording of previous events; Reporting; Research; Research Personnel; Resistance; Resource Sharing; Risk Factors; Role; Science; Services; Sex Bias; Sex Chromosomes; Sex Differences; Signal Transduction; Smoking; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tumor Suppression; Tumor Suppressor Proteins; Universities; Urology; X Chromosome; Y Chromosome; biological sex; cancer initiation; cancer therapy; cancer type; chromosome Y loss; clinical development; computerized data processing; data integration; data repository; design; digital pathology; druggable target; epigenome; exhaustion; expectation; experience; functional genomics; immune checkpoint blockade; improved; innovation; insight; interest; male; men; mortality; mouse model; neoplastic cell; novel; occupational hazard; programs; response; sex; sex disparity; success; symposium; targeted treatment; translational potential; treatment response; tumor; tumor growth; tumor immunology; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

OVERALL – SUMMARY Bladder cancer (BC) is 3-5 times more common in men even when adjusted for environmental factors such as smoking, the primary risk factor for this disease. The goal of this Program Project Grant (PPG) is to advance our knowledge of “sex as a biological variable (SABV)” in BC, with the ultimate objective of improving patient outcomes by discovering sex-specific drivers that can be targeted therapeutically. Benchmarks of Success and Impact for the Program include identification of key immunological, hormonal, chromosomal, genetic, and epigenetic pathways responsible for sex-driven biological phenotypes in BC to inspire the design of a novel line of BC therapeutics based on each patient’s biological sex. To this end, the PPG will unite three leading laboratories in their respective fields, each tackling the problem of SABV from a unique and complementary standpoint of expertise: immunology, cancer biology/functional genomics, and epigenetics. These three research groups, supported by Cedars-Sinai Medical Center Cancer Center and the Ohio State University Comprehensive Cancer Center, have a proven history of collaboration, with nine joint publications since 2017 and multiple co- authored papers in the pipeline. Project 1 aims to uncover the immunological basis of sex differences in BC, taking advantage of a recent discovery in T cell intrinsic androgen receptor signaling in CD8+ T cell exhaustion. Project 2 will focus on the role of the Y chromosome and the Y-lined epigenetic regulators in driving BC progression and resistance to immune checkpoint blockade (ICB); and Project 3 will investigate tumor suppressing activity of the X chromosome-linked epigenetic regulator and the roles of androgen and estrogen- dependent sex hormone pathways, aiming to elucidate the epigenetic basis of sex differences in BC. All three Projects will be supported by an Administrative Core (Admin Core) and two shared resource Cores – the Systems Pathology Core (Core 1) and the Data Science Core (Core 2). Admin Core will manage and support the entire program by offering administrative and fiscal management support and facilitating communication and scientific interactions. Core 1 will provide state-of-the-art digital pathology services, automated and personalized image analyses, and multiparameter immune monitoring. Core 2 will provide unified data processing, analytical pipelines, data integration, data repository, and statistical consultation. Because male prevalence in cancer incidence and mortality is observed across many other cancer types, our scientific findings will likely have broad implications in cancer medicine far beyond BC.

总体 – 总结 即使根据环境因素（例如， 吸烟是这种疾病的主要危险因素。该计划项目补助金 (PPG) 的目标是推进我们的 不列颠哥伦比亚省“性别作为生物变量（SABV）”的知识，最终目标是改善患者 通过发现可以作为治疗目标的性别特异性驱动因素来获得结果。成功的基准和 该计划的影响包括识别关键的免疫学、激素、染色体、遗传和 负责 BC 性别驱动生物表型的表观遗传途径，以激发新品系的设计 根据每位患者的生物性别进行 BC 治疗。为此，PPG 将联合三个领先的 各自领域的实验室，每个实验室都以独特且互补的方式解决 SABV 问题 专业观点：免疫学、癌症生物学/功能基因组学和表观遗传学。这三项研究 团体，由雪松西奈医疗中心癌症中心和俄亥俄州立大学综合分校支持 癌症中心拥有悠久的合作历史，自 2017 年以来已发表九份联合出版物，并有多项合作 正在撰写论文。项目 1 旨在揭示 BC 性别差异的免疫学基础， 利用 T 细胞内在雄激素受体信号传导在 CD8+ T 细胞耗竭中的最新发现。 项目 2 将重点研究 Y 染色体和 Y 系表观遗传调节因子在驱动 BC 中的作用 进展和对免疫检查点阻断（ICB）的抵抗；项目3将研究肿瘤 抑制 X 染色体连锁表观遗传调节因子的活性以及雄激素和雌激素的作用 依赖性激素途径，旨在阐明 BC 性别差异的表观遗传基础。全部三个 项目将由一个管理核心（Admin Core）和两个共享资源核心支持 - 系统病理学核心（核心 1）和数据科学核心（核心 2）。管理核心将管理和支持 通过提供行政和财务管理支持以及促进沟通和 科学互动。 Core 1 将提供最先进的自动化和个性化数字病理学服务 图像分析和多参数免疫监测。 Core 2将提供统一的数据处理、分析 管道、数据集成、数据存储和统计咨询。因为男性癌症患病率 在许多其他癌症类型中观察到发病率和死亡率，我们的科学发现可能具有广泛的意义 对癌症医学的影响远远超出了不列颠哥伦比亚省。