Role of Gut-Immune Interactions in Aging-Associated Bladder Cancer

肠道免疫相互作用在衰老相关膀胱癌中的作用

• 批准号: 10429068
• 负责人: Benjamin Leland Woolbright
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF KANSAS 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: 2023-09-12 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429068
• 关键词: 16S ribosomal RNA sequencing; Affect; Age; Aging; Animals; Antibiotics; Back; Biological Assay; Biology; Bladder; Blood; Breast; CD8B1 gene; Cancer Model; Carcinogens; Cell Proliferation; Cells; Chronic; Collaborations; Colon; Combined Modality Therapy; Credentialing; DNA; DNA Damage; Data; Dedications; Deposition; Development; Dextrans; Diagnosis; Disease; Education; Elderly; Excision; Exposure to; Feces; Fluorescein-5-isothiocyanate; Functional disorder; Future; Genetic; Genetic Models; Immune; Immune system; Immunotherapy; Incidence; Inflammaging; Inflammation; Inflammatory; Innate Immune System; Interleukin-8B Receptor; Intervention; Intestinal permeability; K22 Award; Leadership; Life; Link; Lipopolysaccharides; Liver; Macrophage; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Modeling; Monitor; Mus; Neutrophil Activation; Neutrophil Infiltration; Nitrosamines; Operative Surgical Procedures; Outcome; Oxidases; Patients; Phenotype; Plasma; Population; Principal Component Analysis; Production; Public Health; Reactive Oxygen Species; Recurrence; Regulatory T-Lymphocyte; Research; Resolution; Risk; Role; Scientist; Signal Transduction; Solid Neoplasm; Time; Tissues; Translations; Transplantation; Tumor Immunity; Tumor Volume; Tumor stage; Weight; aged; beta diversity; career; cell injury; chemotherapy; comorbidity; comparative; cytokine; fecal microbiome; fecal transplantation; gut bacteria; gut health; gut homeostasis; gut microbiome; gut microbiota; improved; indexing; inhibitor; intervention effect; lipopolysaccharide-binding protein; microbial; microbiome; microbiota; monocyte; mouse model; neutrophil; novel; older patient; pathogen; pharmacologic; prevent; recruit; risk stratification; standard of care; tissue injury; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

ABSTRACT Bladder cancer (BCa) is predominantly a disease of aging with the risk of developing invasive disease peaking in the 8th decade of life. Elderly patients have higher rates of co-morbidities and are thus often not suitable candidates for standard of care surgery and/or chemotherapy or immunotherapy. Moreover, unlike other cancers such as breast and colon, BCa in the elderly is more aggressive and associated with poorer outcomes. Aging is also associated with both increased baseline levels of tissue inflammation and major differences in the gut microbiome. Aging-associated changes in the microbiome and inflammation have been linked to cancer incidence and progression, and poorer outcomes with immunotherapy and chemotherapy in multiple cancers. In spite of the numerous studies describing these changes, mechanistic studies attempting to understand how these changes impact BCa are comparatively absent. To investigate this phenomenon in a translational setting, we exposed young (8 weeks at start) and older mice (78 weeks at start) to the model BCa carcinogen N-Butyl- N-(4-hydroxybutyl) nitrosamine (BBN). We found older animals had increased baseline levels of inflammation and developed larger, more aggressive tumors after 16 weeks of BBN. Older animals also had more inflamed tumors as we found higher levels of recruited neutrophils and macrophages. Innate immune cells, particularly neutrophils, have been associated with a pro-tumorigenic phenotype in colon, liver, and other cancers and thus we proposed altered inflammation may be a cause of the larger tumors. As aging results in major changes in microbial diversity, we also evaluated 16S sequencing of the fecal microbiome to determine if these animals underwent similar changes. While the microbiomes were similar at the start of the study, we found major divergences between the groups over time, with significant differences in ß-diversity between young or old animals with cancer. This has led to the hypothesis that gut dysfunction drives neutrophil recruitment to enhance BCa formation in aged animals. In Specific Aim 1, I will assess gut dysfunction and microbial divergence over time in young and old animals. In Specific Aim 2, I will use fecal microbiota transplantation to determine if switching microbiota constituency between young and old animals during tumor formation can affect BCa tumorigenesis. In Specific Aim 3, I will use pharmacological and genetic inhibition of specific aspects of neutrophil biology to evaluate the role of neutrophils in BCa development in young and old mice. Completion of these aims will provide the first murine model for aging related increases in BCa. Moreover, this research sets the stage for future R01 studies aimed at detailed mechanistic studies understanding the signaling mechanisms that mediate these observations as well as studies using combination therapy with immunotherapy as a novel treatment for BCa. Dedicated time to perform these studies will serve as the critical preliminary data to propel the applicant, Dr. Ben Woolbright, towards an independent career.

摘要 膀胱癌（BCa）主要是一种衰老性疾病， 在生命的第八个十年。老年患者的合并症发生率较高，因此通常不适合 标准护理手术和/或化疗或免疫疗法的候选者。此外，与其他癌症不同， 如乳腺癌和结肠癌，老年人的BCa更具侵略性，与较差的结果相关。衰老是 也与组织炎症的基线水平增加和肠道的主要差异有关 微生物组微生物组和炎症的衰老相关变化与癌症有关 在多种癌症中，免疫疗法和化疗的发病率和进展以及较差的结果。在 尽管有大量的研究描述了这些变化，但试图了解这些变化是如何发生的机制研究， 这些变化对BCa的影响是相对缺乏的。为了在翻译环境中研究这一现象， 我们将年轻小鼠（开始时8周）和老年小鼠（开始时78周）暴露于模型BCa致癌物N-丁基， N-（4-羟丁基）亚硝胺（BBN）。我们发现年龄较大的动物炎症的基线水平增加 并且在16周的BBN后发展出更大、更具侵袭性的肿瘤。年龄较大的动物也有更多的发炎 肿瘤，因为我们发现更高水平的招募中性粒细胞和巨噬细胞。先天免疫细胞，特别是 嗜中性粒细胞与结肠癌、肝癌和其它癌症中的促肿瘤发生表型相关， 我们认为炎症改变可能是肿瘤变大的原因之一。随着年龄的增长， 微生物多样性，我们还评估了粪便微生物组的16 S测序，以确定这些动物是否 经历了类似的变化。虽然在研究开始时微生物组是相似的，但我们发现， 随着时间的推移，不同群体之间的差异，年轻人或老年人之间的差异显著 患有癌症的动物这导致了这样的假设，即肠道功能障碍驱动中性粒细胞募集，以增强 老年动物中的BCa形成。在具体目标1中，我将评估肠道功能障碍和微生物分歧， 年轻和年老的动物。在具体目标2中，我将使用粪便微生物群移植来确定是否 在肿瘤形成期间，在年轻和年老动物之间切换微生物群组成可以影响BCa 肿瘤发生在具体目标3中，我将使用中性粒细胞特定方面的药理学和遗传学抑制， 生物学来评估嗜中性粒细胞在年轻和老年小鼠中BCa发育中的作用。实现这些目标 将提供第一个与BCa老化相关的小鼠模型。此外，这项研究为以下方面奠定了基础： 未来的R 01研究旨在详细的机制研究，了解介导 这些观察结果以及使用联合治疗与免疫治疗作为新的治疗方法的研究， BCa。专门的时间来执行这些研究将作为关键的初步数据，以推动申请人， 博士本·伍尔布莱特走向独立事业