Aging and Prostate Cancer Risk--the Role of T Cell Dysfunction

衰老与前列腺癌风险——T 细胞功能障碍的作用

• 批准号: 8231413
• 负责人: LINDA A DEGRAFFENRIED
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231413
• 关键词: Address; Age; Aging; Aging-Related Process; Androgens; Animal Model; Cancer Etiology; Cancer Model; Cell physiology; Cessation of life; Chemopreventive Agent; Comorbidity; Data; Development; Diet; Disease; Disease Progression; Elderly; Epidemiologic Studies; Etiology; Event; Family history of; Foundations; Functional disorder; Immune system; Inflammation; Inflammatory; Knock-out; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Obesity; PTEN gene; Pathology; Pathway interactions; Phenotype; Physical activity; Population; Prevention approach; Preventive; Process; Production; Prostate; Public Health; Race; Risk Factors; Role; Serum; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Animals; Transgenic Model; Tumor Suppressor Proteins; aging population; base; cancer cell; cancer initiation; cancer risk; cytokine; immune function; in vivo; insight; men; neoplastic cell; novel; response; tool; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Prostate cancer is the most common non-skin cancer among men in most western populations, and it is the second leading cause of cancer death among U.S. men. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Epidemiological studies have established advancing age, race, and a family history of prostate cancer as risk factors, while many putative risk factors, including androgens, diet, physical activity, sexual factors, inflammation, and obesity have been implicated, but their roles in prostate cancer etiology remain unclear. A significant impediment to developing effective preventive approaches against prostate cancer is the lack of a clear understanding as to the mechanisms by which these risk factors influence disease development and progression. The mechanisms by which aging impacts tumorigenesis are especially understudied, due to the complexities and co-morbidities associated with the aging process. This is especially true in the case of understanding how an aging immune system modulates prostate cancer initiation and progression. Relevant models in which specific components of the aging immune system can be recapitulated are critical for delineating the relationship between aging and tumorigenesis and studying the specific mechanisms by which aging modulates the disease process. Based upon the current understanding of the role of pro-inflammatory pathways in promoting tumorigenesis and our preliminary data demonstrating an induction of these pathways in prostate cancer cells in response to sera from a model of an aging immune system, we hypothesize that the altered immune function in the aging T lymphocyte may not merely be a passive, permissive event in tumor development, but may actively contribute to and promote prostate cancer initiation and progression through changes induced in the prostate cancer microenvironment. We propose to develop a highly unique and novel transgenic animal model to investigate how an aging immune system promotes prostate cancer initiation and progression. We will then assess how the changes in T cell function associated with aging modulate prostate cancer development. This model will be an invaluable tool for developing effective approaches for prevention and treatment of this pervasive disease, and will provide significant insight into the etiology and progression of the second leading cause of cancer deaths in men in the US.

描述（由申请人提供）： 前列腺癌是大多数西方人群中男性最常见的非皮肤癌，也是美国男性癌症死亡的第二大原因。尽管其发病率高，前列腺癌的病因仍然在很大程度上未知。流行病学研究已经确定年龄增长、种族和前列腺癌家族史为风险因素，而许多推定的风险因素，包括雄激素、饮食、身体活动、性因素、炎症和肥胖都有牵连，但它们在前列腺癌病因中的作用仍不清楚。开发有效预防前列腺癌方法的一个重要障碍是缺乏对这些风险因素影响疾病发展和进展的机制的明确理解。由于与衰老过程相关的复杂性和共病性，衰老影响肿瘤发生的机制尤其未得到充分研究。在了解衰老的免疫系统如何调节前列腺癌的发生和发展的情况下，尤其如此。衰老免疫系统的特定成分可以重现的相关模型对于描绘衰老和肿瘤发生之间的关系以及研究衰老调节疾病过程的特定机制至关重要。基于目前对促炎途径在促进肿瘤发生中的作用的理解，以及我们的初步数据表明前列腺癌细胞对衰老免疫系统模型的血清的反应中诱导了这些途径，我们假设衰老T淋巴细胞的免疫功能改变可能不仅仅是肿瘤发展中的被动、允许事件，但是可以通过在前列腺癌微环境中诱导的变化积极地促进和促进前列腺癌的发生和发展。我们建议开发一种非常独特和新颖的转基因动物模型，以研究衰老的免疫系统如何促进前列腺癌的发生和发展。然后，我们将评估与衰老相关的T细胞功能的变化如何调节前列腺癌的发展。该模型将成为开发预防和治疗这种普遍性疾病的有效方法的宝贵工具，并将为美国男性癌症死亡的第二大原因的病因和进展提供重要见解。