Interleukin-1 and Steroid Signaling Drive Toxoplasma-induced Prostatic Hyperplasia

Interleukin-1 和类固醇信号传导驱动弓形虫诱发的前列腺增生

• 批准号: 10352452
• 负责人: Gustavo A Arrizabalaga
• 金额: $ 50.66万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352452
• 关键词: Adult; Anabolism; Androgen Receptor; Androgens; Automobile Driving; Benign Prostatic Hypertrophy; Biological Models; CYP17A1 gene; Cell Proliferation; Cells; Characteristics; Chronic; Data; Development; Epithelial; Estrogen Receptors; Estrogens; Exhibits; Gland; Growth; Growth Factor; Histologic; Hormonal; Human; Hyperplasia; Increased frequency of micturition; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Like Growth Factor I; Interleukin-1; Knowledge; Lesion; Mediating; Methods; Modeling; Molecular; Mus; Nodule; Pathologic; Pathology; Pathway interactions; Pattern; Pharmacology; Play; Process; Production; Prostate; Prostatic; Prostatic Diseases; Prostatic hypertrophy; Publishing; Regimen; Research; Rodent; Role; Signal Transduction; Specimen; Steroid biosynthesis; Steroids; Structure; Symptoms; T-Lymphocyte; Terminology; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; associated symptom; cytokine; design; druggable target; in vivo; intraepithelial; lower urinary tract symptoms; macrophage; men; p38 Mitogen Activated Protein Kinase; prospective; response; steroid hormone; steroid hormone biosynthesis; urinary

Abstract Inflammation is very common in the adult prostate and it is associated with the development of benign prostatic hyperplasia (BPH). We do not know what the primary causes of inflammation in the prostate are, and we do not understand how it promotes prostate disease in men, but proposed mechanisms include released molecules from inflammatory cells that promote prostatic growth, and increases in steroid hormone levels made within the prostate in response to inflammation. The lack of a complete model system that mimics all aspects of human BPH is a key reason for this knowledge gap. Among the pathological features of advanced and highly symptomatic BPH are characteristic proliferative ringlet structures of intraepithelial hyperplasia termed “microglandular hyperplasia”. This terminology arises from the histological structures of small “micro” glands forming within epithelial nodules. Unlike other models of inflammation-induced hyperplasia of the rodent prostate, our recently published Toxoplasma gondii model of prostatic inflammation induces this histological patterning that is observed in humans, and is associated with symptoms similar to human BPH including increased urinary frequency and decreased urinary volumes. This suggests that mechanisms that induce both cell proliferation and tissue patterning might connect inflammation to hyperplasia and prostate disease, and our T. gondii model, which induces both components, would allow us to test this idea. Our hypothesis is that T. gondii-induced chronic prostatic inflammation promotes hyperplasia by promoting cytokine-mediated growth factor signaling and de novo biosynthesis of estrogen and testosterone. Prostatic hyperplasia in humans is associated with increased activity of IL-1 and IGF-1. Therefore in our first aim, we propose to determine if chronic inflammation induced by T. gondii infection induces proliferation in the prostate by activating the IL-1 to IGF-1 pathway. In this aim, we will employ a combination of molecular and pharmacological methods to assess the in vivo expression and production of inflammation-induced IL-1 and IGF-1 associated with hyperplasia and urinary symptoms in T. gondii-infected prostates. In the second aim, we will determine if T. gondii -induced microglandular hyperplasia results from induction of de novo steroid synthesis in the prostate, and we will assess the role of the druggable targets CYP17A1 and androgen and estrogen receptors in this process. We will also investigate the mechanism of how T. gondii induces steroid synthesis. Finally, we will determine if CYP17A1-driven steroid synthesis is associated with inflammation and microglandular hyperplasia in human BPH. It is known that de novo synthesis of androgen and estrogen occurs in prostates with BPH. We will finish with a prospective analysis of prostate tissue from men with BPH compared to non-diseased men to determine if inflammation, hyperplasia, and cytokine and growth factor expression, correlate with steroid synthesis in the prostate and lower urinary tract symptoms characteristic of BPH in men.

摘要 炎症在成人前列腺中非常常见，并且与良性前列腺的发展相关 增生（BPH）。我们不知道前列腺炎症的主要原因是什么，我们不知道 了解它如何促进男性前列腺疾病，但提出的机制包括释放分子 从炎症细胞，促进前列腺生长，并增加类固醇激素水平，使内 前列腺对炎症的反应缺乏一个完整的模型系统，模仿人类的各个方面， BPH是造成这种知识差距的一个关键原因。在晚期和高度恶性的病理特征中， 有症状BPH是上皮内增生的特征性增生小环结构，称为 “微腺增生”。这个术语来自于小的“微型”腺体的组织结构 在上皮结节内形成。不同于其他模型的炎症诱导的啮齿类动物增生 前列腺，我们最近发表的弓形虫前列腺炎症模型诱导这种组织学 在人类中观察到的模式，并与类似于人类BPH的症状相关，包括 尿频和尿量减少。这表明诱导这两种机制的机制 细胞增殖和组织模式可能将炎症与增生和前列腺疾病联系起来， T.同时诱导这两种成分的弓形虫模型将使我们能够验证这一想法。我们假设T. gondii诱导的慢性前列腺炎症通过促进精氨酸介导的生长促进增生 因子信号传导和雌激素和睾酮的从头生物合成。人类前列腺增生是 与IL-1和IGF-1活性增加相关。因此，在我们的第一个目标中，我们建议确定， T.弓形虫感染通过激活IL-1诱导前列腺增殖， IGF-1通路。在这个目标中，我们将采用分子和药理学方法相结合，以评估 与增生相关的炎症诱导的IL-1和IGF-1的体内表达和产生， T.前列腺感染在第二个目标中，我们将确定T.弓形虫感染 微腺增生是由前列腺中类固醇从头合成的诱导引起的，我们将 评估药物靶点CYP 17 A1以及雄激素和雌激素受体在这一过程中的作用。我们 并探讨T.弓形虫诱导类固醇合成。最后，我们将确定 CYP 17 A1驱动的类固醇合成与人类炎症和微腺增生相关 前列腺增生。已知在患有BPH的前列腺中发生雄激素和雌激素的从头合成。我们将完成 通过对BPH患者与非BPH患者的前列腺组织进行前瞻性分析， 如果炎症、增生、细胞因子和生长因子的表达与类固醇的合成相关， 前列腺和下尿路症状的特征性前列腺增生的男性。