Bedside to bench resources for lower urinary tract research

下尿路功能障碍（LUTD）是人类报告的泌尿适应症的集合，包括尿急、间歇性和微弱的尿流、不完全的膀胱排空和增加的排尿频率。男性LUTD的一个主要原因是良性前列腺增生（BPH），这是医学管理与五个α还原酶抑制剂或α-肾上腺素能受体拮抗剂。两种药物都没有将症状进展减少34%以上，而且大多数老年男性除了手术别无选择。前列腺阻塞尿流可导致膀胱逼尿肌过度活动（DO），这是一种知之甚少的疾病，治疗方法大多无效。在过去的40年里，由于前列腺和膀胱功能障碍导致的LUTS的医学管理几乎没有改善，因为我们未能捕获可提供可行治疗靶点的细胞类型特异性分子改变。该提案将解决推导人类LUTD分子机制的根本障碍。在目标1中，我们将产生关于人类LUTD中细胞类型特异性分子变化的多组学数据。我们将把这些数据链接到一个由OpenSpecimen软件管理的组织库，让研究人员可以搜索到超过3,000个临床注释的正常和患病人体标本。在目标2中，我们将设计新的小鼠品系，以实现Cre在特定膀胱，尿道和前列腺基质细胞中的表达。现有的小鼠品系不可能在膀胱基质细胞中过表达或敲除基因而不在前列腺和尿道中引入相同的遗传变化，反之亦然。因此，前列腺和膀胱对排尿的独特贡献不能被孤立。我们将通过创造在成纤维细胞和平滑肌中具有选择性诱导Cre表达的新小鼠品系来克服这个问题。最后，我们将通过将所有方法、工具、数据和协议整合到NIDDK ATLAS数据中心，确保所有资源都是公平的（可查找、可扩展、可互操作和可重用）。所提出的资源是重要的，因为它们建立了基本的床旁到实验室资源，以生成和测试关于人体组织中LUTD机制和合理设计的小鼠模型的假设。

Lower urinary tract dysfunction (LUTD) is a constellation of human-reported urinary indications, including urgency, intermittent and weak urinary stream, incomplete bladder emptying, and increased voiding frequency. A major cause of male LUTD is benign prostatic hyperplasia (BPH), which is medically managed with five alpha reductase inhibitors or alpha-adrenergic receptor antagonists. Neither drug reduces symptomatic progression by more than 34% and most of these elderly men have no option but surgery. Prostatic obstruction of urine flow can lead to bladder detrusor overactivity (DO), a poorly understood disease with largely ineffective therapeutic options. The medical management of LUTS due to prostate and bladder dysfunction has seen little improvement over the past 40 years because we have failed to capture the cell type-specific molecular alterations that would provide actionable therapeutic targets. This proposal will address fundamental barriers to deriving molecular mechanisms of human LUTD. In Aim 1 we will produce multi-omic data on cell type-specific molecular changes in human LUTD. We will link the data to a tissue repository managed with OpenSpecimen software, giving researchers searchable access to >3,000 clinically annotated normal and diseased human specimens. In Aim 2 we will engineer new mouse strains to achieve Cre expression in specific bladder, urethra, and prostate stromal cells. It is not possible with existing mouse strains to overexpress or knockout a gene in a bladder stromal cell without introducing the same genetic change in prostate and urethra, or vice versa. Accordingly, the unique contributions of prostate and bladder to urinary voiding cannot be isolated. We will overcome this problem by creating new mouse strains with selective inducible Cre expression in fibroblasts and smooth muscle. Finally, we will ensure that all resources are FAIR (Findable, Accessible, Interoperable, and Reusable) by incorporating all methods, tools, data and protocols into the NIDDK ATLAS Data Center. The proposed resources are significant because they establish foundational bedside to bench resources to generate and test hypotheses about LUTD mechanisms in human tissues and rationally designed mouse models.