Prostatitis and Prostate Cancer Development

前列腺炎和前列腺癌的发展

• 批准号: 8258692
• 负责人: Lawrence Fong
• 金额: $ 41.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258692
• 关键词: Acute Prostatitis; Adenocarcinoma; Affect; Alleles; Animal Model; Antibody Formation; Antigens; Atypia; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Markers; Biopsy; Cessation of life; Chronic; Chronic Prostatitis; Clinical; Colorectal; Data; Development; Disease; Engineering; Epitopes; Etiology; Foundations; Frequencies; Genetic; Genetically Engineered Mouse; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologics; Inflammation; Inflammatory; Knockout Mice; Large T Antigen; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Mus; Nature; PTEN gene; Pancreas; Papillary; Patients; Pelvic Pain; Prostate; Prostatic; Prostatic Intraepithelial Neoplasias; Proteins; Role; Self Tolerance; Seminal Vesicles; Simian virus 40; Stomach; T cell response; Testing; Thyroid Gland; Tissues; To autoantigen; Transgenic Mice; Wild Type Mouse; Work; autoreactivity; chronic pelvic pain; disease diagnosis; insight; men; mouse model; novel; novel strategies; prostate cancer prevention; prostatitis; recombinase; tumor; tumor progression

DESCRIPTION (provided by applicant): Prostatitis and prostate cancer are extremely common diseases in men, but the relationship between these two diseases is unknown. While acute prostatitis is thought to be infectious in nature, the etiology of chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) and asymptomatic inflammatory prostatitis remains unclear. By studying Aire-deficient mice that have defective immune tolerance and develop spontaneous prostatitis, we have identified a novel prostate autoantigen. Moreover, we have found that CP/CPPS patients with biopsy-proven inflammation in their prostate glands possess immune responses to the analogous human protein, semenogelin (Sg). These results provide new evidence to support autoimmunity as a potential cause for chronic prostatitis. Moreover, by assessing for immune responses to Sg, we may be able to detect prostate inflammation in symptomatic or asymptomatic men. Animal models as well as clinical observations demonstrate that chronic inflammation can enhance the development or certain tumors. We hypothesize that chronic prostatitis contributes to prostate cancer development. The overall objectives of this proposal are to examine: 1) whether there is an association between an immune responses to the prostate autoantigen Sg and prostate cancer in humans; and 2) whether chronic inflammation can enhance the development of prostate cancer in mouse models. In specific aim 1, we will determine whether immune responses to Sg are associated with the presence of inflammation and/or prostate cancer in men undergoing prostate biopsy. In the specific aim 2, we will determine whether chronic prostatitis can alter the development of tumors in mouse models of prostate cancer. This proposal will provide insight in the role of chronic inflammation and prostate cancer development. Moreover, these results could provide a rationale for prostate cancer prevention by treating chronic prostatitis. PUBLIC HEALTH RELEVANCE: Chronic inflammation is thought to contribute to the development of many different malignancies, but the role of inflammation in prostate cancer is unknown. Prostate cancer is the most common non-skin cancer in men. Chronic prostatitis is also an extremely common problem in men. By using a mouse model with a genetic deficiency that predisposes these mice to autoimmune disease, we have identified a protein target for the immune system that we believe to be important in chronic prostatitis in humans. We propose to assess for immune responses to this protein in men who are undergoing prostate biopsies. We will evaluate whether immune responses to this protein are associated with prostate inflammation and prostate cancer on biopsy. We will also determine whether prostatitis can accelerate the development of tumors in mice that are genetically engineered to develop spontaneous prostate cancer. In doing so, we may understand how autoimmunity can contribute to prostate cancer. Moreover, this work could provide the foundation for developing an approach to prostate cancer prevention.

描述（由申请人提供）：前列腺炎和前列腺癌是男性极为常见的疾病，但是这两种疾病之间的关系尚不清楚。虽然急性前列腺炎本质上是传染性的，但慢性前列腺炎和慢性骨盆疼痛综合征（CP/CPPS）的病因尚不清楚。通过研究缺乏免疫耐受性并发展自发前列腺炎的AIRE缺陷小鼠，我们已经确定了一种新型的前列腺自身抗原。此外，我们发现，前列腺腺体炎症的CP/CPP患者对类似的人蛋白塞木凝素（SG）具有免疫反应。这些结果为支持自身免疫性作为慢性前列腺炎的潜在原因提供了新的证据。此外，通过评估对SG的免疫反应，我们可能能够检测到有症状或无症状男性的前列腺炎症。动物模型以及临床观察结果表明，慢性炎症可以增强发育或某些肿瘤。我们假设慢性前列腺炎有助于前列腺癌的发展。该提案的总体目标是检查：1）对人类对前列腺自身抗原SG的免疫反应与人类前列腺癌之间是否存在关联； 2）慢性炎症是否可以增强小鼠模型中前列腺癌的发展。在特定目标1中，我们将确定对SG的免疫反应是否与接受前列腺活检的男性中的炎症和/或前列腺癌有关。在特定目标2中，我们将确定慢性前列腺炎是否可以改变前列腺癌小鼠模型中肿瘤的发展。该提案将为慢性炎症和前列腺癌发展的作用提供洞察力。此外，这些结果可以通过治疗慢性前列腺炎来为预防前列腺癌的理由提供理由。 公共卫生相关性：慢性炎症被认为会导致许多不同的恶性肿瘤的发展，但是炎症在前列腺癌中的作用尚不清楚。前列腺癌是男性最常见的非皮肤癌。在男性中，慢性前列腺炎也是一个极为普遍的问题。通过使用具有使这些小鼠易于自身免疫性疾病的遗传缺乏的小鼠模型，我们已经确定了免疫系统的蛋白质靶标，我们认为这在人类的慢性前列腺炎中很重要。我们建议评估正在进行前列腺活检的男性中对这种蛋白质的免疫反应。我们将评估对该蛋白质的免疫反应是否与活检中的前列腺炎症和前列腺癌有关。我们还将确定前列腺炎是否可以加速在基因上进行自发前列腺癌的基因设计的小鼠的发育。通过这样做，我们可能会了解自身免疫如何有助于前列腺癌。此外，这项工作可以为开发预防前列腺癌的方法提供基础。