Paracrine Regulation of BPH Pathogenesis

描述（由申请人提供）：良性前列腺增生（BPH）是成年男性发病的重要原因，是人类最常见的症状性肿瘤样疾病。临床上，前列腺增生导致尿道收缩，导致尿流速度减慢，无法正确排空膀胱。在西方世界，前列腺增生并不会危及生命。然而，这是一种与发病率和随之而来的医疗费用相关的疾病。前列腺增生导致各种问题，包括夜尿症、尿频、尿急和尿后滴尿，更严重的是，它会导致肾功能不全（血清肌酐升高）、频繁的尿路感染和尿脓毒症（由于尿引流不足）。几十年来，BPH研究的核心一直围绕着雄激素和雌激素信号。这些研究导致了51-还原酶抑制剂如非那雄胺和杜他雄胺的开发。然而，这些方向在开发改善患者状况的新方法方面并没有显示出很大的进展。为了推动该领域向前发展，迫切需要新的概念。该建议的中心假设是前列腺炎症导致间质改变，从而导致局灶性良性腺体扩张。这项工作的长期目标是确定可以单独作为化学预防形式或与当前标准BPH治疗一起提供安全和长期症状缓解的途径。该提案涉及最近公布的NIDDK前列腺研究战略计划中的一些高优先级建议，包括；创造新模式；对前列腺中多种细胞类型之间的信号、相互作用和串扰的理解的发展；并且，表征疾病相关的潜在治疗应用的细胞通路。本提案的三个具体目标涉及BPH发病机制的连锁方面。第一个目标是观察炎症细胞因子表达对前列腺上皮和间质分化的影响。第二个目的是研究这些变化对骨髓来源细胞群募集的影响，以及它们在增生性生长中的作用。第三个目的是研究核因子κ B作为影响BPH发病机制的一种策略。

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is an important cause of orbidity in the adult male population and is the most common symptomatic tumor-like condition in humans. Clinically BPH results in urethral constriction with a consequent slowing of urinary flow rates and an inability to properly empty the urinary bladder. In the Western world BPH is not a life threatening condition. However, it is a condition with significant associated morbidity and consequent healthcare costs. BPH results in a variety of problems including nocturia, frequency, urgency and post-mictural dribbling and, more seriously it can cause renal insufficiency (with rising serum creatinine), frequent urinary tract infections and urosepsis due to insufficient urinary draining. For many decades the core of research into BPH has centered around androgen and estrogen signaling. These studies have given rise to the development of 51-reductase inhibitors such as finasteride and dutasteride. However these directions have not shown much recent progress in developing new approaches to improve the situation of patients. New concepts are sorely needed to move the field forwards. The central hypothesis of this proposal is that prostatic inflammation results in a profile of stromal changes which contribute to focal benign glandular expansion. The long term goal of this work is to identify pathways which can be co-targeted ether alone as a form of chemoprevention or along with current standard BPH therapies to provide safe and long term symptomatic relief. This proposal addresses a number of the high priority recommendations of the recently published NIDDK Prostate Research Strategic Plan including; the creation of new models; the development of an understanding of the signaling, interaction and crosstalk between multiple cell types in the prostate; and, the characterization of disease-relevant cellular pathways for potential therapeutic applications. The three specific aims in this proposal address interlocking aspects of BPH pathogenesis. The first aim looks at the effects of inflammatory cytokine expression on prostatic epithelial and stromal differentiation. The second aim examines the consequences of these changes in relation to the recruitment of bone marrow- derived cell populations and the contribution that these play in hyperplastic growth. The third aim examines the targeting of nuclear factor-kappa B as a strategy to influence BPH pathogenesis.