Bedside to bench resources for lower urinary tract research

用于下尿路研究的床边到工作台资源

基本信息

批准号：
10517227
负责人：
Douglas William Strand
金额：
$ 103.93万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517227
关键词：
ATAC-seq Address Adrenergic Antagonists Algorithms Alleles Amino Acids Antibodies Automobile Driving Benign Prostatic Hypertrophy Binding Bladder Bladder Dysfunction C-terminal Cell Nucleus Cells Clinical Clinical Data Computer software Data Data Set Databases Development Disease Elderly Elderly man Engineering Ensure Enterobacteria phage P1 Cre recombinase Exposure to FAIR principles Fibroblasts Foundations Frequencies Functional disorder Gene Expression Genes Genetic Genetic Transcription Genomics Human Image In Situ Individual Joints Knock-out Label Lead Link Lower urinary tract Medical Methods Molecular Mouse Strains Multiomic Data Mus Mutation Myofibroblast N-terminal National Institute of Diabetes and Digestive and Kidney Diseases Obstruction Operative Surgical Procedures Organ Organ Donor Oxidoreductase Pathway Analysis Patients Pharmaceutical Preparations Population Process Prostate Prostatic Prostatic Urethra Protocols documentation Reporting Research Research Personnel Resolution Resources Response Elements Smooth Muscle Specificity Specimen Stream Stromal Cells System Testing Tetracyclines Therapeutic Tissue Banks Tissues Trans-Activators Transgenic Mice Urethra Urine Validation Visualization age effect aged alpha-adrenergic receptor bench to bedside biobank cell type combinatorial computational pipelines data centers data resource genome annotation genome browser genomic locus genomic predictors histological stains human data human disease human tissue inhibitor insight intein male men mouse model open source overexpression promoter prostate enlargement rational design selective expression single cell analysis single-cell RNA sequencing synergism therapeutic target tissue resource tool trait transcription factor urinary

项目摘要

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.

下尿路功能障碍 (LUTD) 是一系列人类报告的泌尿症状，包括尿急、尿流间歇性和微弱、膀胱排空不完全以及排尿频率增加。男性 LUTD 的一个主要原因是良性前列腺增生 (BPH)，可通过五种 α 还原酶抑制剂或 α-肾上腺素能受体拮抗剂进行医学治疗。这两种药物都不能将症状进展减缓超过 34%，而且大多数老年男性除了手术别无选择。前列腺尿流阻塞可导致膀胱逼尿肌过度活动（DO），这是一种人们知之甚少的疾病，且治疗方案大多无效。过去 40 年来，由于前列腺和膀胱功能障碍引起的 LUTS 的医疗管理几乎没有取得任何进展，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，我们将生成有关人类 LUTD 中细胞类型特异性分子变化的多组学数据。我们将把数据链接到由 OpenSpecimen 软件管理的组织存储库，使研究人员能够搜索到超过 3,000 个临床注释的正常和患病人类标本。在目标 2 中，我们将设计新的小鼠品系，以在特定的膀胱、尿道和前列腺基质细胞中实现 Cre 表达。现有的小鼠品系不可能在膀胱基质细胞中过度表达或敲除某个基因，而不在前列腺和尿道中引入相同的基因变化，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。我们将通过培育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个问题。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，确保所有资源都是公平的（可查找、可访问、可互操作和可重用）。所提议的资源非常重要，因为它们建立了基础的床边到工作台资源，以生成和测试有关人体组织中 LUTD 机制的假设和合理设计的小鼠模型。