Leukocytic Phenotypes Associated with BPH Progression

总体：摘要 良性泌尿系统疾病中心的目标是：1）创造和维持一个环境， 通过专注于科学研究，支持良性泌尿学领域的重要和创新研究 项目检查“与BPH进展相关的白细胞表型”，2）教育和告知年轻人 关于BPH的科学家和医生，以及3）开发新的互动项目和合作， 良性泌尿学研究界的其他团体。该计划汇集了基本的专业知识， 科学、生物信息学和临床泌尿学，将新技术应用于良性泌尿学研究领域。 该研究小组包括来自良性和恶性泌尿外科领域以及非泌尿外科领域的成员。 泌尿系统癌症良性前列腺增生（BPH）和相关的下尿路症状（LUTS）是 高度流行，并且随着人口老龄化将变得越来越频繁。大约一个- 三分之一的BPH患者对目前的药物治疗有抵抗力，另外三分之一的初始应答者（约 总患者人群的10%）在初始阳性应答后随后发展为治疗耐药。 因此，对于大约40%的患者人群，没有有效的药物治疗，只剩下手术作为唯一的治疗方法。 治疗选择在美国，每年约有12万例手术用于治疗男性 他们对现有的医疗干预措施有抵抗力。其中许多是老年患者， 严重的合并症，通常不是理想的手术候选人。前列腺增生症与前列腺增生症密切相关， 炎性共病。然而，连接免疫/炎症变化的特征和途径 BPH进展尚不清楚。我们在初步数据中显示，TNFα拮抗剂可以降低 自身免疫性炎症性疾病患者中BPH的发生率表明， 前列腺白细胞信号网络的研究可以阐明新的治疗靶点。这项建议会 利用单细胞（sc）RNA-seq充分表征小前列腺患者的白细胞群， IPSS评分较低vs前列腺较大、症状评分较高和进展至手术的患者， 前列腺增生症这将提供存在的细胞的全面图片，并将允许 生物信息学方法的应用，以确定细胞外信号转导途径，被激活， 这些炎症细胞随着疾病的进展而变化。行政核心协调中心的所有活动， 保持财务和行政监督，管理教育充实计划，负责 教育下一代科学家，并告知科学家和临床医生我们的工作。的 行政核心还与NIDDK和其他IR-BU中心协调，并整合我们的 与更广泛的良性泌尿外科研究界的方法。

OVERALL: SUMMARY The goals of this Center for Benign Urological Diseases are: 1) to create and maintain an environment that supports important and innovative research in the field of benign urology by focusing on a Scientific Research Project examining “Leukocyte phenotypes associated with BPH progression,” 2) to educate and inform young scientists and physicians about BPH, and 3) to develop new interactive projects and collaborations involving other groups in the benign urology research community. The program brings together expertise in basic science, bioinformatics, and clinical urology to apply new technologies in the field of benign urologic research. The research team includes members from the benign and malignant urology fields as well as from non- urologic cancers. Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are highly prevalent and will become increasingly more frequent with an aging demographic. Approximately one- third of BPH patients are resistant to current medical therapy, and a further third of initial responders (around 10% of the total patient population) subsequently develop therapy resistance after an initial positive response. So, for around 40% of the patient population there is no effective medical therapy, leaving surgery as the sole treatment option. Approximately 120,000 surgeries are performed annually in the United States to treat men who are resistant to the available medical interventions. Many of these are elderly patients often with significant co-morbidities who are often not ideal surgical candidates. BPH is closely associated with pro- inflammatory co-morbidities. However, the characteristics and pathways linking immune/inflammatory changes to BPH progression are unclear. We show in preliminary data that TNFα antagonists can reduce the incidence of BPH in patients with autoimmune inflammatory conditions suggesting that a more complete understanding of the leukocyte signaling network in the prostate could elucidate new therapeutic targets. This proposal will utilize single-cell (sc)RNA-seq to fully characterize the leukocyte population in patients with small prostates and low IPSS scores vs. those with large prostates, high symptom scores, and progression to surgery specifically for a BPH indication. This will provide a comprehensive picture of the cells that are present and will allow for the application of bioinformatics approaches to define the extracellular signaling pathways that are activated in these inflammatory cells as disease progresses. The Administrative Core coordinates all Center activities, maintains financial and administrative oversight, manages the Educational Enrichment Program charged with the education of the next generation of scientists, and informs scientists and clinicians of our work. The Administrative Core also coordinates with the NIDDK and the other IR-BU Centers and integrates our approaches with the wider benign urologic research community.