Androgen Regulation of Colonic Motility

项目总结 肠易激综合征(IBS)是一种常见的、令人衰弱的疾病，在 临床表现和治疗结果知之甚少。我研究的长期目标是 该计划旨在确定导致IBS和其他疾病性别差异的细胞和分子机制 以便为患者开发更有针对性和有效的治疗方法。性激素，比如 由于雄激素睾酮和5-α-双氢睾酮，在男性和女性之间自然不同，可以 解释IBS的性别差异。先前的研究表明，雄激素水平与IBS相关。 症状，如腹痛和大便频率改变。雄激素传统上被认为是男性 生殖激素在很大程度上仍不清楚它们在肠道内稳态中起什么作用。 确定肠道中雄激素信号的正常功能对于理解为什么男性和 女性受到IBS的影响不同，正在开发更好的治疗方法。 这一建议建立在我们的初步数据基础上，这些数据表明，内源性神经元中的一大子集 结肠的神经回路表达雄激素受体，并扰乱雄性小鼠的雄激素水平 会显著减慢肠道运动。这项应用的目标是确定雄激素信号是如何在 肠神经系统(ENS)的这些神经元改变了结肠的运动。对于目标1，我们将使用雄激素 受体敲除小鼠确定肠神经元雄激素信号在多大程度上调节结肠 能动性。对于目标2，我们将确定性腺雄激素的缺失如何改变肠道神经元的功能。 结肠中的神经源性运动模式。这项工作的最主要的理由是，确定 ENS中的雄激素信号将阐明荷尔蒙缺乏如何改变消化健康。这些研究 提出了将IBS临床研究中的相关观察转化为 对循环雄激素缺乏如何导致胃肠动力障碍的病理生理学理解。 这项工作的发现不仅将促进对胃肠道动力的基本理解，而且还将揭示 靶向雄激素信号通路作为一种新的、更有效和个性化的治疗潜力 肠易激综合征的治疗探讨。

PROJECT SUMMARY Irritable bowel syndrome (IBS) is a common and debilitating disorder with marked sex differences in clinical presentation and treatment outcomes that are poorly understood. The long-term goal of my research program is to identify the cellular and molecular mechanisms that underlie sex differences in IBS and other digestive disorders in order to develop more targeted and effective therapies for patients. Sex hormones, such as the androgens testosterone and 5α-dihydrotestosterone, naturally vary between men and women and could explain sex differences in IBS. Previous studies have suggested that androgen levels correlate with IBS symptoms, such as abdominal pain and altered stool frequency. Androgens are traditionally considered male reproductive hormones and it remains largely unknown what role they play in intestinal homeostasis. Determining the normal functions of androgen signaling in the gut is crucial for understanding why men and women are differentially affected by IBS and developing better treatments. This proposal builds on our preliminary data, which show that a large subset of neurons in the intrinsic nerve circuits of the colon expresses the androgen receptor, and that disrupting androgen levels in male mice dramatically slows intestinal motility. The objective of this application is to determine how androgen signaling in these neurons of the enteric nervous system (ENS) alters colonic motility. For Aim 1, we will use androgen receptor knockout mice to determine to what extent androgen signaling in enteric neurons regulates colonic motility. For Aim 2, we will determine how loss of gonadal androgens alters the function of enteric neurons in neurogenic motor patterns in the colon. The overarching rationale for this work is that determining the role of androgen signaling in the ENS will shed light on how hormonal deficits alter digestive health. The studies proposed are essential next steps to translating the correlative observations made in clinical studies of IBS into a pathophysiological understanding of how deficits in circulating androgens might cause GI dysmotility. Findings from this work will not only advance the fundamental understanding of GI motility, but also reveal the therapeutic potential of targeting androgen signaling pathways as a new, more effective and personalized approach to the treatment of IBS.