Androgen Regulation of Colonic Motility

项目摘要 肠易激综合征（IBS）是一种常见的和衰弱的疾病，具有显着的性别差异， 临床表现和治疗结果知之甚少。我研究的长期目标是 该项目旨在确定IBS和其他疾病性别差异的细胞和分子机制。 消化系统疾病，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5α-二氢睾酮在男性和女性之间自然变化， 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的 生殖激素，并且它们在肠道内稳态中起什么作用在很大程度上仍然未知。 确定肠道中雄激素信号传导的正常功能对于理解为什么男性和女性在消化道中的作用是至关重要的。 女性受IBS的影响不同，并开发更好的治疗方法。 这一提议建立在我们的初步数据基础上，这些数据表明，内在神经元中的一个大的神经元子集， 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 显著减缓肠蠕动本申请的目的是确定雄激素信号传导在人乳腺癌中的作用。 肠神经系统（ENS）的这些神经元改变结肠运动。对于目标1，我们将使用雄激素 受体敲除小鼠，以确定肠神经元中雄激素信号传导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丢失如何改变肠神经元的功能， 结肠的神经原性运动模式这项工作的首要理由是， ENS中的雄激素信号将揭示激素缺乏如何改变消化系统健康。研究 提出了将IBS临床研究中的相关观察转化为 从病理生理学上了解循环雄激素缺乏如何导致胃肠道动力障碍。 这项工作的发现不仅将促进对GI运动的基本理解，而且还将揭示胃肠运动的机制。 靶向雄激素信号通路作为一种新的、更有效的和个性化的治疗潜力 治疗IBS的方法。

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.