Bedside to bench resources for lower urinary tract research

下尿路功能障碍（LUTD）是人类报告的一系列泌尿指征，包括尿急、间歇性和弱尿流、膀胱排空不完全和排尿频率增加。男性LUTD的主要原因是良性前列腺增生（BPH），医学上用五种α还原酶抑制剂或α肾上腺素能受体拮抗剂治疗。两种药物都不能减少34%以上的症状进展，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，前列腺和膀胱功能障碍引起的LUTS的医疗管理几乎没有改善，因为我们未能捕获细胞类型特异性的分子改变，从而提供可行的治疗靶点。这一建议将解决人类LUTD分子机制推导的基本障碍。在Aim 1中，我们将产生人类LUTD细胞类型特异性分子变化的多组学数据。我们将把这些数据连接到一个由open试样软件管理的组织库，使研究人员能够搜索到3000个临床注释的正常和患病的人类标本。在Aim 2中，我们将设计新的小鼠品系来实现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不引起前列腺和尿道基因改变的情况下过度表达或敲除膀胱间质细胞中的基因，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选择性诱导Cre表达的新小鼠品系来克服这一问题。最后，我们将通过将所有方法、工具、数据和协议纳入NIDDK ATLAS数据中心，确保所有资源都是FAIR（可查找、可访问、可互操作和可重用）的。提出的资源是重要的，因为它们建立了基础的床边到台架资源，以产生和测试关于人体组织中LUTD机制的假设和合理设计的小鼠模型。

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.