Genotypic and Phenotypic Studies of Inflammation in PCPT

PCPT 炎症的基因型和表型研究

• 批准号: 7102931
• 负责人: SCOTT M LIPPMAN
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102931
• 关键词: antioxidants; benign prostate hyperplasia; biopsy; cancer prevention; cancer risk; carcinogenesis; chemoprevention; enzyme linked immunosorbent assay; finasteride; fluorescent in situ hybridization; genetic markers; genetic polymorphism; genotype; growth factor; human data; immunocytochemistry; inflammation; matrix assisted laser desorption ionization; pathologic process; phenotype; prostate neoplasms; sex hormones; tumor promoters; western blottings

DESCRIPTION (provided by applicant): We hypothesize that chronic intraprostatic inflammation contributes to the development of prostate cancer. Chronic inflammation may serve as an initiator and/or promoter of prostate carcinogenesis as it does in infection-associated liver and stomach cancer and in colon cancer in inflammatory bowel disease. Indeed, regions of atrophy showing hyperproliferation and inflammation, called proliferative inflammatory atrophy (PIA) lesions, are common in the prostate. These lesions may be regenerative and may be the result of response to infection or cell trauma due to oxidant damage or hypoxia. To address this hypothesis, we propose to evaluate the association of tissue, circulating, and genetic markers of inflammation, its sources, or sequelae with prostate cancer. Prostate cancer cases and age frequency-matched controls who were negative on an end-of-study biopsy will be selected from among participants in the Prostate Cancer Prevention Trial (PCPT). In biopsy sections from 400 cases and 400 controls, we will determine the prevalence, extent, and biological characteristics of inflammation and atrophy using immunohistochemistry or FISH and image analysis. We will detect antibodies against 5 infectious agents (e.g., Chlamydia trachomatous, Trichomonas vaginalis) by ELISA in serum from 600 cases and 600 controls. We will genotype 1800 cases and 1800 controls for germline polymorphisms in 12 genes involved in the innate and adaptive immune response to infection and tissue damage (e.g., TLR-4, IFNy,IL-10) using MALDI-TOF. We will use logistic regression to estimate the odds ratios of prostate cancer and high-grade disease. Jointly with the other Projects, we will test whether the associations vary by exposure to factors that may alter adverse effects of inflammation, including the PCPT study drug finasteride, levels of serum antioxidants, sex steroid hormones, and growth factors. Given that inflammation is a clear target for intervention, we anticipate that the proposed work will have important implications for prostate cancer prevention. The revised Project addresses all reviewer concerns, including those for new preliminary data on the association of inflammation with prostate cancer in the PCPT and additional immunology expertise.

描述（由申请人提供）：我们假设慢性前列腺内炎症 有助于前列腺癌的发展。慢性炎症可能是前列腺癌发生的引发剂和/或促进剂，就像它在感染相关的肝癌和胃癌以及炎症性肠病中的结肠癌中一样。事实上，显示出过度增殖和炎症的萎缩区域，称为增殖性炎症萎缩（PIA）病变，在前列腺中很常见。这些病变可能是再生性的，并且可能是对感染或氧化损伤或缺氧引起的细胞损伤的反应的结果。为了解决这一假设，我们建议评估炎症的组织、循环和遗传标记、其来源或后遗症与前列腺癌的关联。将从前列腺癌预防试验 (PCPT) 的参与者中选出研究结束时活检呈阴性的前列腺癌病例和年龄频率匹配的对照。在 400 例病例和 400 例对照的活检切片中，我们将使用免疫组织化学或 FISH 和图像分析来确定炎症和萎缩的患病率、程度和生物学特征。我们将通过 ELISA 检测 600 名病例和 600 名对照者血清中针对 5 种感染原（例如沙眼衣原体、阴道毛滴虫）的抗体。我们将使用 MALDI-TOF 对 1800 个病例和 1800 个对照的 12 个基因进行种系多态性基因分型，这些基因涉及对感染和组织损伤的先天性和适应性免疫反应（例如 TLR-4、IFNy、IL-10）。我们将使用逻辑回归来估计前列腺癌和高级别疾病的优势比。我们将与其他项目一起测试协会是否 因接触可能改变炎症不良影响的因素而异，包括 PCPT 研究药物非那雄胺、血清抗氧化剂水平、性类固醇激素和生长因子。鉴于炎症是干预的明确目标，我们预计拟议的工作将对前列腺癌的预防产生重要影响。修订后的项目解决了审稿人的所有担忧，包括 PCPT 中炎症与前列腺癌关联的新初步数据以及其他免疫学专业知识。