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.

项目概要良性前列腺增生（BPH）是老年男性发生的前列腺良性肿大，阻碍膀胱流出。由此产生的下尿路症状，如尿急、尿频和排空不完全，发病率很高，每年的医疗费用高达数十亿。当前的 BPH 治疗不是很有效，因为药物针对的是正常前列腺生理学，而不是 BPH 病理生理学，目前仍知之甚少。下一代疾病靶向治疗将需要对 BPH 发病机制有更详细的了解。在 BPH 临床样本的基因组研究中，我们发现了 BPH 中骨形态发生蛋白 5 (BMP5) 单一、大量过度表达。 BMP、成员 TGF-β超家族在组织形态发生中具有重要作用，尽管BMP5本身尚未被研究广泛研究。在试点单细胞分析中，我们发现了一种特征不明的成纤维细胞类型富含 BPH 基质作为表达 BMP5 的主要细胞。值得注意的是，将重组 BMP5 添加到培养中的前列腺细胞会改变其基因表达谱，使其更类似于我们所知道的基因表达谱。在 BPH 临床标本中观察。根据这些数据，我们假设 BMP5 协调关键 BPH 疾病过程中的分子和细胞变化。因此，消除 BMP5 的疗法信号传导可能为预防或治疗 BPH 提供新的精确方法。为实现这一目标，拟议研究旨在确定 BPH 中前列腺细胞类型和 BMP5 产生的触发因素；定义细胞类型和 BPH 中 BMP5 信号转导受体；确定 BMP5 信号传导的封锁是否逆转 BPH 疾病表型。研究结果将为前列腺细胞和信号传导提供重要的新见解由 BMP5 精心策划，以及 BPH 新疾病靶向疗法的关键验证数据。