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.

膀胱过度活动综合症 (OAB) 在男女和所有年龄段中都有很高的患病率，从病理生理学角度来看，OAB 的特点是膀胱平滑肌（逼尿肌）自发收缩。 ，以及伴随的膀胱壁增厚，目前针对 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 β3 激动剂，以减少尽管这些药物已被证明是有效和安全的，但仍达到了一定的治疗上限，这反映在对现有药物治疗的依从性较低，对逼尿肌收缩和增生的认识的提高为了解逼尿肌收缩和增生提供了基础。 Rac GTP 酶是一组小单体 GTP 酶，被证明参与广泛的生理过程，在这些功能中，Rac 亚型已被证明参与其中。不同器官中平滑肌收缩和细胞周期的调节。我们小组的最新研究结果证明了 Rac 的作用，它可以促进人类前列腺平滑肌收缩和前列腺平滑肌细胞生长。可以合理地假设，Rac 在膀胱中具有类似的功能。因此，该项目旨在找出 Rac 抑制剂（NSC23766、EHT1864）对 1) 人类逼尿肌组织收缩、2) 培养的膀胱平滑肌细胞生长和 3) 的影响。大鼠的排尿参数。

项目成果

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

通过药物干预抑制非肾上腺素能前列腺平滑肌收缩的新策略

• DOI: 10.1002/pros.23780
• 发表时间: 2019-05-01
• 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
• 通讯作者: M. Hennenberg

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

Rac 抑制剂 EHT1864 和 NSC23766 对女性和男性人类逼尿肌平滑肌收缩的抑制

• 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: Bingsheng Li;Qingfeng Yu;Ruixiao Wang;C. Gratzke;Xiaolong Wang;A. Spek;A. Herlemann;A. Tamalunas;F. Strittmatter;R. Waidelich;C. Stief;M. Hennenberg
• 通讯作者: M. Hennenberg

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

Rac1 沉默、NSC23766 和 EHT1864 会减少膀胱平滑肌细胞的生长和肌动蛋白组织。

• DOI: 10.1016/j.lfs.2020.118468
• 发表时间: 2020-09-19
• 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
• 通讯作者: M. Hennenberg