BMP5 cells and signaling in BPH pathogenesis

BMP5 细胞和 BPH 发病机制中的信号传导

基本信息

批准号：
10250334
负责人：
JAMES D. BROOKS
金额：
$ 23.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250334
关键词：
5 Alpha-Reductase Inhibitor Adrenergic Receptor Androgens Award BMP5 gene Benign Benign Prostatic Hypertrophy Bladder Cells Clinical Coculture Techniques Data Disease Drug Targeting Epithelial Epithelial Cells Fibroblasts Finasteride Frequencies Functional disorder Funding Gene Expression Genetic Genomics Goals Health Care Costs Hyperplasia Individual Industry Inflammation Knowledge Medical Methods Molecular Morbidity - disease rate Morphogenesis Muscle Tonus Nodule Pathogenesis Pathogenicity Pathway interactions Phenotype Physiology Pre-Clinical Model Process Production Prostate Prostatic Prostatic Epithelium Published Comment RNA Interference Recombinants Role Sampling Signal Pathway Signal Transduction Slice Smooth Muscle Specimen Stromal Cells Tissue Model Tissues Transforming Growth Factor beta Translating Validation Work bone morphogenetic protein receptors burden of illness cell type disease phenotype experimental study improved inhibitor/antagonist innovation insight knock-down lower urinary tract symptoms member men molecular phenotype neutralizing antibody next generation older men overexpression personalized approach prevent prostate enlargement receptor single cell analysis small molecule tamsulosin targeted treatment therapeutic target transcriptome

项目摘要

PROJECT SUMMARY 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. Next generation, disease-targeted therapies will require a more detailed knowledge of BPH pathogenesis. In genomic studies of BPH clinical samples, we discovered a singular, massive overexpression of Bone Morphogenetic Protein 5 (BMP5) in BPH. BMPs, members of the TGF-beta superfamily, have important roles in tissue morphogenesis, though BMP5 itself has not been extensively studied. In pilot single-cell analyses, we identified a poorly characterized fibroblast cell type enriched in BPH stroma as the principle cell expressing BMP5. Remarkably, addition of recombinant BMP5 to prostatic cells in culture alters their gene-expression profiles to more closely resemble the profiles that we observe in the BPH clinical specimens. From these data, we hypothesize that BMP5 orchestrates key molecular and cellular changes underlying the BPH disease process. As such, therapies that abrogate BMP5 signaling may provide a new precision approach to prevent or treat BPH. Towards that goal, the proposed studies aim to Define the prostatic cell type and triggers of BMP5 production in BPH; Define the cell types and receptors for BMP5 signal transduction in BPH; and Determine whether blockade of BMP5 signaling reverses BPH disease phenotypes. Study findings will provide important new insight into the prostatic cells and signaling orchestrated by BMP5, and key validation data towards new disease-targeted therapies for BPH.