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.

年龄是良性前列腺增生（BPH）的主要危险因素，BPH是一种进行性疾病， 随着男性年龄的增长，患病率不断上升，影响到70%的60岁男性和90%的80岁男性。 BPH可导致膀胱出口梗阻和下尿路梗阻，严重影响患者的生活质量 症状（LUTS）表现为前列腺尿道流量减少和膀胱排空不完全 导致更频繁的排尿，特别是在晚上（排尿）。分子机制负责 BPH/LUTS尚不清楚，这延迟了治疗开发。相关血清中的与糖尿病相关的变化 睾酮（T）和雌二醇（E2）水平与BPH/LUTS相关。T和E2是主要的贡献者， BPH/LUTS的启动和进展通过1）核受体调节基因表达 （经典信号通路）或2）快速激活激酶级联并改变 细胞过程（非经典信号）。 我们的初步研究确定了一个新的范式来解释持续的前列腺平滑肌 引起尿流限制和LUTS的收缩。使用3种BPH/LUTS模型， 在T和E2水平下，我们发现蛋白磷酸酶1调节因子（PPP 1 r）的表达发生了一致的变化， 降低或预计降低肌球蛋白轻链磷酸酶（MLCP）的活性， 前列腺平滑肌（SM）松弛和膀胱排尿。这一重要进展确定了PPP 1 r 蛋白质和其他SM松弛调节剂作为逆转衰老相关BPH/LUTS的治疗靶点。 在目标1中，我们将鉴定PPP 1 r蛋白和其他松弛促进途径的成员， 在老年小鼠前列腺模型和人BPH组织/细胞培养物中差异调节。在目标2中， 将确定T和E2介导的途径所需的启动和维持BPH和LUTS使用我们的 仅具有经典或仅非经典E2信号传导或仅经典T信号传导的转基因小鼠。 我们的研究结果将为前列腺尿道周围持续的SM收缩提供机械解释， 尿流限制和LUTS，包括排尿功能障碍，发生与年龄相关的改变 荷尔蒙水平我们的研究结果将确定BPH/LUTS进展所需的途径和过程， 确定LUTS治疗的新靶点。