Steroid Hormone Pathways Regulating BPH and LUTS

调节 BPH 和 LUTS 的类固醇激素途径

• 批准号: 10601867
• 负责人: Paul S. Cooke
• 金额: $ 48.95万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601867
• 关键词: Adverse effects; Affect; Age; Aging; Anatomy; Androgen Receptor; Androgens; Apoptosis; Benign Prostatic Hypertrophy; Biochemical; Biological Assay; Bladder; Cell Proliferation; Cell physiology; Cells; Characteristics; Chronic; Disease; Estradiol; Estrogens; Etiology; Frequencies; Functional disorder; Gene Expression; Goals; Hormones; Human; Hyperplasia; Mediating; Mediator; Membrane; Messenger RNA; Modeling; Molecular; Mus; Muscle Contraction; Muscle relaxation phase; Mutate; Nocturia; Nuclear Receptors; Obstruction; Operative Surgical Procedures; Pathway interactions; Pharmacotherapy; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Premature aging syndrome; Prevalence; Primary Cell Cultures; Process; Progressive Disease; Proliferating; Prostate; Prostatic; Prostatic Diseases; Prostatic Urethra; Protein phosphatase; Proteins; Quality of life; Regulation; Relaxation; Resources; Risk Factors; Serum; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Testing; Testosterone; Tissues; Transgenic Mice; Universities; Urethra; Urination; Urine; Urology; Wisconsin; age related; aged; hormonal signals; in vivo; lower urinary tract symptoms; member; men; micturition urgency; mouse model; myosin phosphatase; novel; prevent; prostate enlargement; protein expression; receptor; response; steroid hormone; targeted treatment; therapy development; tissue/cell culture; tool; urinary

Aging is a major risk factor for benign prostate hyperplasia (BPH), a progressive disease that occurs with increasing prevalence as men age, affecting 70% of men in their sixties and 90% of men in their eighties. Quality of life is severely impacted by BPH, which leads to bladder outlet obstruction and lower urinary tract symptoms (LUTS) presenting as reduced flow through the prostatic urethra and incomplete bladder emptying resulting in more frequent urination, especially at night (nocturia). Molecular mechanisms responsible for BPH/LUTS are unclear, which has delayed treatment development. Age-related changes in relative serum testosterone (T) and estradiol (E2) levels are associated with BPH/LUTS. T and E2 are major contributors to BPH/LUTS initiation and progression that act through 1) nuclear receptors to regulate gene expression (classical signaling pathway) or 2) membrane receptors that rapidly activate kinase cascades and alter cellular processes (nonclassical signaling). Our preliminary studies identify a new paradigm to explain sustained prostatic smooth muscle contraction that causes restriction of urine flow and LUTS. Using 3 models of BPH/LUTS with aged levels of T and E2, we found consistent altered expression of protein phosphatase 1 regulators (PPP1r) that decrease or are predicted to decrease activity of myosin light chain phosphatase (MLCP) required for prostatic smooth muscle (SM) relaxation and bladder voiding. This important advance identifies PPP1r proteins and other SM relaxation regulators as targets for therapies to reverse aging associated BPH/LUTS. In Aim 1, we will identify PPP1r proteins and other members of the relaxation promoting pathway that are differentially regulated in aged mouse prostate models and human BPH tissues/cell cultures. In Aim 2, we will identify the T- and E2-mediated pathways required to initiate and sustain BPH and LUTS by using our transgenic mice having only classical or only nonclassical E2 signaling or only classical T signaling. Our results will provide a mechanistic explanation for sustained SM contraction around the prostatic urethra, restriction of urine flow and LUTS including voiding dysfunction that occurs with aging-related altered hormone levels. Our findings will identify pathways and processes required for BPH/LUTS progression and identify new targets for LUTS therapies.

衰老是良性前列腺增生（BPH）的主要危险因素，这是一种进行性疾病，发生在 随着男性的年龄，六十年代的男性中有70％的男性和八十年代的男性中有90％的患病率增加。 生活质量受到BPH的严重影响，BPH会导致膀胱出口阻塞并降低尿路 症状（LUTS）以减少前列腺尿道的流量减少和不完整的膀胱排空 导致排尿更频繁，尤其是在晚上（夜尿）。负责的分子机制 BPH/LUT尚不清楚，这延迟了治疗发展。相对血清年龄相关的变化 睾丸激素（T）和雌二醇（E2）水平与BPH/LUTS有关。 T和E2是 BPH/LUTS的启动和进展，通过1）核受体来调节基因表达 （经典信号通路）或2）快速激活激酶级联反应并改变的膜受体 细胞过程（非经典信号传导）。 我们的初步研究确定了一种新的范式来解释持续的前列腺平滑肌 导致尿液流量和LUTS的限制的收缩。使用3种型号的BPH/LUTS T和E2的水平，我们发现蛋白质磷酸酶1调节剂（PPP1R）的表达持续改变， 减少或预计会减少肌球蛋白轻链磷酸酶（MLCP）的活性 前列腺平滑肌（SM）松弛和膀胱空隙。这个重要的进步确定了PPP1R 蛋白质和其他SM松弛调节剂是逆转衰老相关的BPH/LUTS的靶标。 在AIM 1中，我们将确定PPP1R蛋白质和放松的其他成员促进途径 在老年小鼠前列腺模型和人类BPH组织/细胞培养物中受到差异调节。在AIM 2中，我们 将确定通过使用我们的T-和E2介导的途径来启动和维持BPH和LUTS 仅具有经典或非经典E2信号传导或仅经典t信号传导的转基因小鼠。 我们的结果将为前列腺尿道周围持续的SM收缩提供一个机械解释， 尿流和LUT的限制，包括随着衰老相关的变化而发生的空白功能障碍 激素水平。我们的发现将确定BPH/LUTS进展所需的途径和过程 确定LUTS疗法的新目标。