Role of Rac-GTPases for human detrusor contraction, growth of detrusor cells, and urodynamic regulation in vivo: mechanistic and functional investigations in preclinical models

Rac-GTPase 对人逼尿肌收缩、逼尿肌细胞生长和体内尿动力学调节的作用：临床前模型的机制和功能研究

• 批准号: 386787056
• 负责人: Professor Dr. Christian Gratzke
• 金额: --
• 依托单位: Urologische Klinik und Poliklinik (Campus Großhadern)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/386787056?language=en
• 关键词: Role; Rac; GTPases; human; detrusor

Overactive bladder syndrome (OAB) has a high prevalence in both sexes and all age groups, with negative impact on a person´s quality of life. From a pathophysiologic point of view, OAB is characterized by spontaneous contractions of bladder smooth muscle (detrusor), and concomitant bladder wall thickening. Current first line treatment options for irritative lower urinary tract symptoms (LUTS) caused by OAB include anticholinergics and beta3-agonists, to reduce detrusor contractions and symptoms. Even though these drugs have been shown to be effective and safe, a certain therapeutic ceiling has been reached, which is reflected by low adherence to these established medical therapies. Improved knowledge of detrusor contraction and hyperplasia provides the basis for understanding of current limits in therapy, and for development of future therapies.Rac GTPases are a group of small monomeric GTPases shown to participate in a broad spectrum of physiological processes. Among these functions, Rac isoforms have been proven to be involved in regulation of smooth muscle contraction and cell cycle in different organs. Latest findings from our group demonstrated a role of Rac, which promotes human prostate smooth muscle contraction and prostate smooth muscle cell growth. It appears reasonable to assume, that Rac has similar functions in bladder smooth muscle. Therefore, this project aims to find out effects of Rac inhibitors (NSC23766, EHT1864) on 1) contraction of human detrusor tissue, 2) growth of cultured bladder smooth muscle cells, and 3) micturition parameters in rats.

膀胱过度活动综合征（OAB）在男女和所有年龄组中都有很高的患病率，对一个人的生活质量有负面影响。从病理生理学的角度来看，OAB的特征在于膀胱平滑肌（逼尿肌）的自发性收缩和伴随的膀胱壁增厚。目前OAB引起的刺激性下尿路症状（LUTS）的一线治疗选择包括抗胆碱能药物和β 3-受体激动剂，以减少逼尿肌收缩和症状。尽管这些药物已被证明是有效和安全的，但已经达到了一定的治疗上限，这反映在对这些既定医学疗法的低依从性上。逼尿肌收缩和增生的知识的提高为了解目前治疗的局限性和未来治疗的发展提供了基础。Rac GTPases是一组小的单体GTPases，参与广泛的生理过程。在这些功能中，Rac异构体已被证明参与调节不同器官中的平滑肌收缩和细胞周期。我们小组的最新发现证明了Rac的作用，它促进人类前列腺平滑肌收缩和前列腺平滑肌细胞生长。这似乎是合理的假设，Rac在膀胱平滑肌中具有类似的功能。因此，本项目旨在了解Rac抑制剂（NSC 23766、EHT 1864）对1）人类逼尿肌组织收缩、2）培养膀胱平滑肌细胞生长和3）大鼠排尿参数的影响。

项目成果

Rac1 silencing, NSC23766 and EHT1864 reduce growth and actin organization of bladder smooth muscle cells.

• DOI: 10.1016/j.lfs.2020.118468
• 发表时间: 2020-09
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Ruixiao Wang;Qingfeng Yu;Xiaolong Wang;Bingsheng Li;A. Ciotkowska;B. Rutz;Yiming Wang;C. Stief;M. Hennenberg

New strategies for inhibition of non‐adrenergic prostate smooth muscle contraction by pharmacologic intervention

• DOI: 10.1002/pros.23780
• 发表时间: 2019-05
• 期刊: The Prostate
• 作者: Qingfeng Yu;C. Gratzke;Yiming Wang;Xiaolong Wang;Bingsheng Li;F. Strittmatter;A. Herlemann;Ruixiao Wang;A. Tamalunas;R. Waidelich;C. Stief;M. Hennenberg

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

• DOI: 10.3389/fphar.2020.00409
• 发表时间: 2020-04-07
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Li Bingsheng;Yu Qingfeng;Hennenberg, Martin
• 通讯作者: Hennenberg, Martin