Fibroblast subsets in BPH pathogenesis

BPH 发病机制中的成纤维细胞亚群

• 批准号: 10297622
• 负责人: JONATHAN R POLLACK
• 金额: $ 33.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297622
• 关键词: 5 Alpha-Reductase Inhibitor; ATAC-seq; Address; Adrenergic Receptor; Affect; Androgens; Atlases; Automobile Driving; BMP5 gene; Benign; Benign Prostatic Hypertrophy; Biological Markers; Biological Models; Bladder; CXCL13 gene; Categories; Cell Communication; Cells; Chromatin; Clinical; Communities; Data; Differentiation and Growth; Disease; Drug Targeting; Elements; Embryo; Embryonic Development; Enhancers; Epithelial; Epithelial Cells; Fibroblasts; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Genomics; Goals; Growth; Health Care Costs; Histology; Immunohistochemistry; Inflammation; Inflammatory Response; Injury; Knowledge; Ligands; Magnetic Resonance Imaging; Maps; Medical; Methods; Mining; Morbidity - disease rate; Multiplexed Ion Beam Imaging; Mus; Muscle Tonus; Myofibroblast; Neighborhoods; Normal tissue morphology; Pathogenesis; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Physiology; Precision therapeutics; Prostate; Prostatic hypertrophy; Regulation; Research; Resources; Sampling; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Smooth Muscle; Specimen; Symptoms; Therapeutic; Time; Tissue Model; Tissues; Urethra; Urology; base; comparative; genetic signature; lower urinary tract symptoms; new technology; older men; overexpression; preclinical study; prostate enlargement; receptor; response to injury; targeted treatment; transcriptome; transcriptome sequencing; urinary

ABSTRACT – PROJECT 1 Benign Prostatic Hyperplasia (BPH) is the benign enlargement of the prostate gland that occurs in older men, obstructing bladder outflow. The resultant lower urinary tract symptoms, such as urgency, frequency and incomplete emptying, have considerable morbidity, and carry annual healthcare costs in the Billions. Current BPH treatments are not very effective because the drugs target normal prostate physiology but not BPH pathophysiology, which is still poorly understood. New disease-targeted therapies will require a more detailed knowledge of BPH pathogenesis. In genomic studies of BPH clinical samples, we discovered a stromal gene signature that correlated with BPH symptoms, and an enrichment of fibroblasts overexpressing signaling proteins BMP5 and CXCL13. Fibroblast BMP5 enhanced prostate epithelial proliferation and drove gene expression profiles to mimic BPH tissue. From these data, we hypothesize that BPH is driven (at least in part) by pathogenic fibroblast cell subset(s), where defining those subsets will provide important new opportunities for disease targeted therapies. Towards that goal, the proposed studies aim to Define the fibroblast subsets in BPH versus normal prostate; Determine the key interactions between BPH fibroblast subsets and prostate epithelium that drive prostate enlargement; and Distinguish between BPH origins in embryonic re-awakening versus injury response. Study findings will provide new understanding of the contribution of prostate stroma to BPH pathogenesis, and identify new strategies for targeted treatment.

摘要-项目1 良性前列腺增生（BPH）是发生在老年男性中的前列腺良性增大， 阻塞膀胱流出。由此产生的下尿路症状，如尿急、尿频和 不完全排空，具有相当高的发病率，并且每年的医疗费用高达数十亿美元。电流 前列腺增生的治疗不是很有效，因为药物的目标是正常的前列腺生理，但不是前列腺增生 病理生理学，这仍然是知之甚少。新的疾病靶向治疗将需要更详细的 了解BPH发病机制。在BPH临床样本的基因组研究中，我们发现了一个基质基因， 与BPH症状相关的信号，以及过度表达信号的成纤维细胞的富集 蛋白质BMP 5和CXCL 13。成纤维细胞BMP 5促进前列腺上皮细胞增殖及驱动基因 表达谱以模拟BPH组织。根据这些数据，我们假设BPH是由（至少部分） 病原性成纤维细胞亚群，其中定义这些亚群将提供重要的新机会 用于疾病靶向治疗。为了实现这一目标，拟议的研究旨在定义成纤维细胞亚群， BPH与正常前列腺;确定BPH成纤维细胞亚群和前列腺之间的关键相互作用 上皮细胞驱动前列腺肥大;以及区分胚胎再觉醒中的BPH起源 与损伤反应的对比。研究结果将为前列腺间质在前列腺增生中的作用提供新的认识。 BPH发病机制，并确定新的针对性治疗策略。