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：
10705120
负责人：
Douglas William Strand
金额：
$ 102.72万
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/10705120
关键词：
ATAC-seq 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 Frequencies Functional disorder Gene Expression Genes Genetic Genetic Transcription Genomics Human Image In Situ Individual Joints Knock-out Label 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 improved inducible Cre 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）是人类报告的尿液适应症的星座，包括紧迫性，间歇性和弱尿流，不完整的膀胱排空以及增加空隙频率。雄性LUTD的主要原因是良性前列腺增生（BPH），该增生症（BPH）由五个α还原酶抑制剂或α-肾上腺素能受体拮抗剂进行医学管理。两种药物都不会将症状的进展减少超过34％，而这些老年男性大多数除了手术外别无选择。前列腺阻塞尿流会导致膀胱逼尿肌过度活动（DO），这是一种疾病，疾病的治疗方法不足。在过去的40年中，由于前列腺和膀胱功能障碍而引起的LUT的医疗管理几乎没有改善，因为我们未能捕获可提供可行的治疗靶标的细胞类型特异性分子改变。该提案将涉及得出人LUTD分子机制的基本障碍。在AIM 1中，我们将产生有关人LUTD中细胞类型特异性分子变化的多词数据。我们将将数据链接到使用OpenSpececemen软件管理的组织存储库，从而使研究人员可以搜索> 3,000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菌株以在特定的膀胱，尿道和前列腺基质细胞中实现CRE表达。现有小鼠菌株不可能在膀胱基质细胞中过表达或敲除基因而不引入前列腺和尿道的遗传变化，反之亦然。因此，无法隔离前列腺和膀胱对尿液排尿的独特贡献。我们将通过在成纤维细胞和平滑肌中创建具有选择性诱导CRE表达的新小鼠菌株来克服这个问题。最后，我们将通过将所有方法，工具，数据和协议合并到NIDDK ATLAS数据中心中，确保所有资源都公平（可访问，可互操作和可重复使用）。提出的资源很重要，因为它们为基础资源建立了基础床边，以生成和检验有关人体组织中LUTD机制和理性设计的小鼠模型的假设。