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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.

项目摘要良性前列腺增生（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。下一代疾病靶向治疗将需要更详细的了解BPH的发病机制。在BPH临床样本的基因组研究中，我们发现了一个 BPH中骨形态发生蛋白5（BMP 5）的单一、大量过度表达。BMPs， TGF-β超家族在组织形态发生中具有重要作用，尽管BMP 5本身并不重要。被广泛研究。在试验性单细胞分析中，我们发现了一种特征不明显的成纤维细胞类型，在BPH基质中富集作为表达BMP 5的主要细胞。值得注意的是，将重组BMP 5添加到培养物中的前列腺细胞改变了它们的基因表达谱，使其更接近我们所知的基因表达谱在BPH临床标本中观察。根据这些数据，我们假设BMP 5协调了关键的分子和细胞的变化，BPH疾病的过程。因此，消除BMP 5的疗法信号传导可以提供一种新的精确方法来预防或治疗BPH。为实现这一目标，研究旨在确定前列腺细胞类型和BPH中BMP 5产生的触发因素;确定细胞类型和 BPH中BMP 5信号转导的受体;并确定阻断BMP 5信号转导是否逆转 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BMP 5精心策划，以及针对BPH的新疾病靶向治疗的关键验证数据。