Role of Insulin Receptor-mediated Signaling In Underactive Bladder

摘要： 膀胱活动不足（UAB）或逼尿肌活动不足（DU）在老年人中很常见， 储存和排泄症状。UAB的治疗选择非常有限，通常情况下， 功效糖尿病（DM）是众所周知的导致UAB，然而，潜在的分子机制， 关于DM如何导致UAB的问题尚不清楚。胰岛素信号在新陈代谢中起着至关重要的作用， 耐药性是DM的关键特征。除了维持代谢平衡，最近的进展表明， 胰岛素信号传导对于基因转录、细胞增殖/分化和细胞存活也很重要， 也不同组织中的胰岛素抵抗被发现是导致肝脏高血糖、心脏高血糖和心脏高血糖的原因。 衰竭、骨骼肌萎缩和高脂血症。这些活动通过调节多种信号传导而发生 包括FOXO信号通路。然而，胰岛素信号在膀胱组织中的作用还没有得到很好的研究， 膀胱胰岛素抵抗在UAB发病机制中的作用尚不清楚。在这里，我们是第一个提出， 胰岛素抵抗或膀胱组织本身胰岛素信号传导的中断直接导致发病 糖尿病膀胱功能障碍（DBD），导致UAB。为了验证这一假设，我们生成了一个 组成型杂合平滑肌特异性胰岛素受体（SMIR +/-）缺陷小鼠模型以模拟 膀胱平滑肌的胰岛素抵抗。我们的初步数据表明，SMIR +/-小鼠 膀胱表型模仿DBD/UAB，表明胰岛素抵抗在DBD/UAB发病机制中的关键作用。在 因此，我们将建立一个条件性基因敲除小鼠，以特异性地删除平滑肌中的IR基因 在他莫昔芬诱导下。该模型将在成人BSM中产生IR信号传导缺陷，因此更多 与人类糖尿病膀胱非常相似。我们将使用这种动物模型来研究它在颞叶中的作用。 开发DBD/UAB。我们将确定：（1）BSM中的IR缺失是否显著影响BSM的表达。 通过测量葡萄糖/脂质代谢和血清胰岛素水平来检测动物的总体代谢紊乱;（2） BSM中IR介导的信号传导缺陷是否是DBD/UAB表型发病机制的基础 膀胱形态、膀胱功能和BSM收缩性。我们将进一步确定潜在的 通过研究（1）FoxO家族成员，（2）FoxO 对细胞凋亡至关重要的调节分子，和（3）对平滑肌结构和功能至关重要的分子。 本研究将确定BSM中的胰岛素信号传导如何影响其生长、存活、收缩性和整体功能。 膀胱功能，并为我们提供了新的见解，胰岛素抵抗如何导致DBD/UAB。这 知识将是重要的发展潜在的新的治疗策略，以治疗膀胱症状。

Abstract: Underactive bladder (UAB) or detrusor underactivity (DU) is common in elderly people, and causes distressing storage and voiding symptoms. Treatment options for UAB are extremely limited and generally have poor efficacy. Diabetes mellitus (DM) is well known to cause UAB, however, the underlying molecular mechanism on how DM leads to UAB is not understood. Insulin signaling plays a crucial role in metabolism, and insulin resistance is a key feature in DM. In addition to maintaining metabolic homeostasis, recent progress indicates that insulin signaling is also important for gene transcription, cell proliferation/differentiation, and cell survival, as well. Insulin resistance in different tissues was found to be responsible for hepatic hyperglycemia, cardiac failure, skeletal muscle atrophy, and hyperlipidemia. These activities occur by regulating multiple signaling pathways, including FOXO signaling. However, the role of insulin signaling in bladder tissue is not well studied, and bladder insulin resistance in the pathogenesis of UAB is unknown. Here we are the first to propose that insulin resistance, or disruption of insulin signaling in bladder tissue itself, directly underlies the pathogenesis of diabetic bladder dysfunction (DBD), leading to UAB. To test this hypothesis, we have generated a constitutive heterozygous smooth muscle specific insulin receptor (SMIR+/-) deficient mouse model to mimic the insulin resistance in bladder smooth muscle (BSM). Our preliminary data indicate that SMIR+/- mouse bladder phenocopies DBD/UAB, suggesting a crucial role of insulin resistance in DBD/UAB pathogenesis. In this proposal, we will generate a conditional knockout mouse to specifically delete IR gene in smooth muscle under tamoxifen induction. This model will generate IR signaling deficiency in adult BSM and therefore more closely mimics the human diabetic bladder. We will use this animal model to study its role in the temporal development of DBD/UAB. We will determine: (1) whether IR deletion in BSM contributes significantly to the overall metabolic disorders of the animal by measuring glucose/lipid metabolism, and serum insulin level; (2) whether deficiency of IR mediated signaling in BSM underlies the pathogenesis of DBD/UAB by phenotyping bladder morphology, bladder function, and BSM contractility in these mice. We will further define the potential underlying mechanism in these IR signaling deficiency mice, by studying (1) FoxO family members, (2) FoxO regulated molecules crucial for apoptosis, and (3) molecules critical for smooth muscle structure and function. This study will determine how insulin signaling in BSM impacts its growth, survival, contractility, and the overall bladder function, and provide us with new insights into how insulin resistance leads to DBD/UAB. This knowledge will be important for developing potential novel therapeutic strategies to treat bladder symptoms.!