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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)是人类报告的一系列尿路指征，包括尿流急促、间歇和微弱，膀胱排空不全，以及排尿频率增加。男性LUTD的主要原因是良性前列腺增生症(BPH)，药物治疗使用五种α-还原酶抑制剂或α-肾上腺素能受体拮抗剂。这两种药物都没有减少34%以上的症状进展，这些老年男性中的大多数除了手术别无选择。前列腺尿流阻塞可导致膀胱逼尿肌过度活动(DO)，这是一种知之甚少的疾病，治疗方案大多无效。在过去的40年里，由于前列腺和膀胱功能障碍导致的LUT的医疗处理几乎没有改善，因为我们未能捕捉到提供可操作治疗靶点的特定细胞类型的分子变化。这项建议将解决人类LUTD分子机制推导的根本障碍。在目标1中，我们将产生关于人类LUTD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经过临床注释的3000个正常和疾病人类标本。在目标2中，我们将设计新的小鼠品系，以实现Cre在特定的膀胱、尿路和前列腺基质细胞中的表达。在现有的小鼠品系中，如果不在前列腺和尿路中引入相同的基因变化，就不可能在膀胱基质细胞中过度表达或敲除基因，反之亦然。因此，前列腺和膀胱对排尿的独特贡献是不能孤立的。我们将通过创造新的小鼠品系来克服这个问题，这些品系在成纤维细胞和平滑肌中具有选择性诱导的Cre表达。最后，通过将所有方法、工具、数据和协议整合到NIDDK ATLAS数据中心，我们将确保所有资源都是公平的(可查找、可访问、可互操作和可重复使用)。建议的资源具有重要意义，因为它们建立了基础的床边到工作台资源，以生成和测试关于人类组织中LUTD机制的假设，并合理设计小鼠模型。