Examining the role of defective oxidative phosphorylation in the normal and diseased prostate

检查氧化磷酸化缺陷在正常和患病前列腺中的作用

基本信息

批准号：
10679629
负责人：
Alexis Elizabeth Adrian
金额：
$ 3.73万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679629
关键词：
Address Adrenergic alpha-Antagonists Affect Age Aging Antioxidants Automobile Driving Benign Prostatic Hypertrophy Biological Assay Cell Line Cells Collagen Complex Data Defect Development Disease Electrodes Epithelium Exhibits FDA approved Fibrosis Functional disorder Future Genetic Genotype Genus Hippocampus Goals Health Care Costs Human Immunochemistry Immunohistochemistry Increased frequency of micturition Intervention Knock-out Knowledge Liver Lower urinary tract LoxP-flanked allele MAPK8 gene Measures Medical Metabolism Mitochondria Mitochondrial Proteins Modeling Mus NADH dehydrogenase (ubiquinone)Oleic Acids Outcome Oxidative Phosphorylation Oxygen Consumption Pathologic Pathology Pathway interactions Patient Care Patients Pharmaceutical Preparations Process Proliferating Prostate Prostatic Prostatic Diseases Quality of life Reactive Oxygen Species Respiration Risk Factors Role Running Sampling Signaling Molecule Sirius Red F3B Spottings Stains Stromal Cells Testosterone 5-alpha-Reductase Time Tissues Transforming Growth Factor beta Up-Regulation Work aged biomarker development improved in vivo interest loss of function lower urinary tract symptoms men mitochondrial dysfunction mitochondrial metabolism mortality risk mouse model novel protein complex urinary

Address Adrenergic alpha-Antagonists Affect Age Aging Antioxidants Automobile Driving Benign Prostatic Hypertrophy Biological Assay Cell Line Cells Collagen Complex Data Defect Development Disease Electrodes Epithelium Exhibits FDA approved Fibrosis Functional disorder Future Genetic Genotype Genus Hippocampus Goals Health Care Costs Human Immunochemistry Immunohistochemistry Increased frequency of micturition Intervention Knock-out Knowledge Liver Lower urinary tract LoxP-flanked allele MAPK8 gene Measures Medical Metabolism Mitochondria Mitochondrial Proteins Modeling Mus NADH dehydrogenase (ubiquinone)Oleic Acids Outcome Oxidative Phosphorylation Oxygen Consumption Pathologic Pathology Pathway interactions Patient Care Patients Pharmaceutical Preparations Process Proliferating Prostate Prostatic Prostatic Diseases Quality of life Reactive Oxygen Species Respiration Risk Factors Role Running Sampling Signaling Molecule Sirius Red F3B Spottings Stains Stromal Cells Testosterone 5-alpha-Reductase Time Tissues Transforming Growth Factor beta Up-Regulation Work aged biomarker development improved in vivo interest loss of function lower urinary tract symptoms men mitochondrial dysfunction mitochondrial metabolism mortality risk mouse model novel protein complex urinary

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项目摘要

ABSTRACT Lower urinary tract symptoms (LUTS) are a significant burden to aging men and are often as a result of benign prostatic hyperplasia (BPH). While BPH/LUTS is not commonly fatal with proper medical intervention, it does cause a significant reduction in quality of life for many men as they age. Furthermore, BPH/LUTS increases risk of mortality and results in billions of dollars in healthcare costs annually. There is currently a subset of BPH/LUTS patients that fail FDA-approved treatments (α-blockers, 5ARI), and these patients have been shown to have increased prostatic fibrosis. There is no FDA-approved medication targeting fibrosis or the aging process in BPH/LUTS, even though aging is the greatest risk factor. This proposal aims to develop a better understanding about the role of aging, fibrosis, and mitochondrial dysfunction in BPH/LUTS. Mitochondrial dysfunction is a hallmark of both aging and fibrosis and has not been thoroughly studied in relation to BPH/LUTS. Preliminary data suggests that oxidative phosphorylation (OXPHOS) is a mitochondrial pathway contributing to cellular dysfunction in BPH/LUTS. Aim 1 of this proposal intends to investigate the connection between OXPHOS disruption and lower urinary tract dysfunction (LUTD) in a novel mouse model. Aim 2 of this proposal will investigate the connection between OXPHOS disruption and pathways associated with fibrosis, using genetic loss-of-function cell line models. Finally, Aim 3 will work to identify a new pathway of interest for treatment, using oleic acid as a mitochondrial metabolism modulator. Collectively, these aims will improve our overall understanding of the processes underlying BPH/LUTS, with a special focus on aging, mitochondrial dysfunction, and fibrosis. This proposal hopes to provide translational outcomes that can eventually improve patient care and treatment options.

抽象的较低的尿路症状（LUTS）对衰老的男性造成了明显的燃烧，通常是良性的前列腺增生（BPH）。虽然BPH/LUTS通常在适当的医疗干预措施中并非致命，但随着年龄的增长，许多男性的生活质量大大降低。此外，BPH/LUTS增加了风险每年的死亡率和数十亿美元的医疗保健费用。目前有BPH/LUT的子集失败FDA批准治疗的患者（α受体阻滞剂，5ARI），这些患者已被证明具有前列腺纤维化增加。没有FDA批准的药物针对纤维化或衰老过程 BPH/LUTS，即使衰老是最大的危险因素。该建议旨在建立更好的理解关于衰老，纤维化和线粒体功能障碍在BPH/LUTS中的作用。线粒体功能障碍是衰老和纤维化的标志，与BPH/LUTS有关。初步的数据表明氧化磷酸化（OXPHOS）是一种有助于细胞的线粒体途径 BPH/LUTS中的功能障碍。该提案的目标1旨在研究Oxphos之间的联系新型小鼠模型中的破坏和较低的尿路功能障碍（LUTD）。该提议的目标2将使用通用性研究Oxphos破坏与纤维化相关的途径之间的联系功能丧失的单元线模型。最后，AIM 3将努力确定一种新的治疗途径油酸作为线粒体代谢调节剂。总的来说，这些目标将改善我们的整体了解BPH/LUTS的过程，特别关注衰老，线粒体功能障碍，和纤维化。该建议希望提供转化结果，有时可以改善患者护理和治疗选择。