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 - 摘要 膀胱癌（BC）在男性中的常见3-5倍，即使对环境因素进行了调整，例如 吸烟，这种疾病的主要危险因素。该计划项目赠款（PPG）的目标是促进我们的 在卑诗省了解“性别为生物变量（SABV）”的知识，其最终目标是改善患者 通过发现可以在历史上找到针对性的性别驱动因素来取得成果。成功的基准和 该计划的影响包括鉴定关键免疫学，荷尔蒙，染色体，遗传和 卑诗省性驱动性生物表型的表观遗传途径激发了新线条的设计 基于每个患者的生物学性别的卑诗省治疗。为此，PPG将团结三个领先 在各自领域的实验室，每个实验室都解决了独特而完整的SABV问题 专业知识的角度：免疫学，癌症生物学/功能基因组学和表观遗传学。这三个研究 小组，由Cedars-Sinai医学中心癌症中心和俄亥俄州立大学综合 癌症中心，具有可靠的合作历史，自2017年以来拥有九本联合出版物，多个共同的共同出版物 撰写了管道中的论文。项目1旨在揭示BC性别差异的免疫学基础， 利用CD8+ T细胞耗尽中T细胞固有的雄激素受体信号传导的最新发现。 项目2将重点介绍Y染色体和Y层表观遗传调节剂在驱动BC中的作用 对免疫检查点阻滞（ICB）的进展和抵抗力；项目3将调查肿瘤 抑制X染色体相关的表观遗传调节剂的活性以及雄激素和雌激素的作用 依赖性骑士途径，旨在阐明BC性别差异的表观遗传基础。这三个 项目将得到管理核心（管理员核心）和两个共享资源核心的支持 - 系统病理核心（核心1）和数据科学核心（核心2）。管理员核心将管理和支持 通过提供行政和财政管理支持并支持沟通以及 科学互动。 Core 1将提供最先进的数字病理学服务，自动化和个性化 图像分析和多参数免疫监测。核心2将提供统一的数据处理，分析性 管道，数据集成，数据存储库和统计咨询。因为癌症的男性患病率 在许多其他癌症类型中都观察到发病率和死亡率，我们的科学发现可能会广泛 癌症医学的影响远远超出了卑诗省。