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.

抽象的 炎症在成人前列腺中非常常见，并且与良性前列腺的发展有关 增生（BPH）。我们不知道前列腺炎症的主要原因是什么，我们也不知道 了解它如何促进男性前列腺疾病，但提出的机制包括释放的分子 来自促进前列腺生长的炎症细胞，以及体内产生的类固醇激素水平增加 前列腺对炎症的反应。缺乏模仿人类各方面的完整模型系统 BPH 是造成这种知识差距的一个关键原因。晚期和高度的病理特征之一 有症状的 BPH 是上皮内增生的特征性增殖小环结构，称为 “微腺体增生”。该术语源自小型“微型”腺体的组织学结构 上皮结节内形成。与其他炎症诱导的啮齿动物增生模型不同 前列腺，我们最近发表的前列腺炎症的弓形虫模型诱导了这种组织学 在人类中观察到的模式，与人类 BPH 类似的症状相关，包括 尿频增加和尿量减少。这表明诱导两者的机制 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，我们的 弓形虫模型可以诱导这两种成分，使我们能够测试这个想法。我们的假设是 T. 弓形虫诱导的慢性前列腺炎症通过促进细胞因子介导的生长来促进增生 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 活性增加有关。因此，在我们的第一个目标中，我们建议确定是否 弓形虫感染引起的慢性炎症通过激活 IL-1 来诱导前列腺增殖 IGF-1 途径。为此，我们将结合分子和药理学方法来评估 与增生相关的炎症诱导的 IL-1 和 IGF-1 的体内表达和产生 弓形虫感染的前列腺出现泌尿系统症状。在第二个目标中，我们将确定弓形虫是否诱导 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 评估药物靶标 CYP17A1 以及雄激素和雌激素受体在此过程中的作用。我们 还将研究弓形虫如何诱导类固醇合成的机制。最后，我们将确定是否 CYP17A1驱动的类固醇合成与人类炎症和微腺增生有关 前列腺肥大。已知患有 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 对患有 BPH 的男性与未患病男性的前列腺组织进行前瞻性分析，以确定 如果炎症、增生、细胞因子和生长因子表达与类固醇合成相关 前列腺和下尿路症状是男性 BPH 的特征。