BMP5 cells and signaling in BPH pathogenesis

项目总结 良性前列腺增生症(BPH)是发生在老年男性的良性前列腺增大， 阻碍膀胱流出。由此产生的下尿路症状，如紧迫感、频率和 不完全排空，有相当高的发病率，每年的医疗成本高达数十亿美元。当前 BPH的治疗不是很有效，因为这些药物针对的是正常的前列腺生理，而不是BPH 病理生理学，目前仍知之甚少。下一代，针对疾病的治疗将需要 对BPH发病机制有更详细的认识。在对BPH临床样本的基因组研究中，我们发现了一种 骨形态发生蛋白5(BMP5)在良性前列腺增生症(BPH)中的单一大量过度表达。BMPS，成员 转化生长因子-β超家族在组织形态发生中发挥重要作用，尽管BMP5本身还没有 经过广泛研究。在试验性单细胞分析中，我们确定了一种特征不佳的成纤维细胞类型。 富含BPH间质，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改变了它们的基因表达谱，使其更接近于我们 在前列腺增生症的临床标本中观察。根据这些数据，我们假设BMP5编排了 BPH疾病过程中潜在的分子和细胞变化。因此，消除BMP5的疗法 信号转导可能为预防或治疗BPH提供一种新的精确方法。为了实现这一目标，拟议的 研究的目的是确定前列腺细胞类型和BMP5产生的触发因素；定义细胞类型和 BMP5信号转导的受体；并确定BMP5信号转导的阻断是否逆转 BPH疾病表型。研究结果将为了解前列腺细胞和信号提供重要的新见解。 由BMP5协调，以及针对BPH的新的疾病靶向治疗的关键验证数据。

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.