Androgen Regulation of Colonic Motility

雄激素对结肠运动的调节

基本信息

批准号：
10214609
负责人：
Meenakshi Rao
金额：
$ 13.28万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214609
关键词：
Abdominal Pain Adolescent Adult Affect Androgen Receptor Androgens Award Castration Cells Chronic Clinical Clinical Research Colon Complex Analysis Constipation Data Defect Development Digestive System Disorders Disease Enteral Enteric Nervous System Estrogens Exhibits Feces Female Frequencies Functional Gastrointestinal Disorders Functional Imaging Funding Gastrointestinal Diseases Gastrointestinal Motility Gastrointestinal Transit Gene Expression Genetic Models Genetic Transcription Goals Gonadal Hormones Gonadal Steroid Hormones Health Hormonal Hormones Human Intestinal Motility Irritable Bowel Syndrome Knockout Mice Length Libido Light Migrating Myoelectric Complex Molecular Motor Mus Myenteric Plexus NOS1 gene Nerve Neurons Nitrergic Neurons Nitric Oxide Nitric Oxide Donors Orchiectomy Outcome Patients Pattern Peripheral Nervous System Peristalsis Phenotype Play Preparation Puberty Receptor Signaling Regulation Research Role Sex Differences Signal Pathway Signal Transduction Smooth Muscle Myocytes Speed Stanolone Supplementation Surgical Models Symptoms Testing Testosterone Therapeutic Time Translating Treatment Efficacy Treatment outcome Water Woman Work androgen sensitive cell motility effective therapy gastrointestinal inhibitor/antagonist intestinal homeostasis male men motility disorder nerve supply neuronal survival personalized approach programs receptor receptor-mediated signaling reproductive hormone sex targeted treatment treatment response

项目摘要

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.

项目摘要肠易激综合症（IBS）是一种常见且令人衰弱的疾病，性别差异明显临床表现和治疗结果知之甚少。我研究的长期目标程序是确定IBS和其他性别差异基础的细胞和分子机制消化系统疾病，以开发患者更有针对性和有效的疗法。性激素，这样的由于雄激素睾丸激素和5α-二氢睾丸激素，男性和女性自然会有所不同，可以解释IBS中的性别差异。先前的研究表明，雄激素水平与IBS相关症状，例如腹痛和粪便频率改变。传统上被认为是男性的生殖骑马，并且在很大程度上尚不清楚它们在肠道稳态中的作用。确定肠道中雄激素信号的正常功能对于理解男性和为什么女性受IB的影响不同，并发展更好的治疗方法。该提案建立在我们的初步数据的基础上，该数据表明，内在的一部分神经元子集结肠的神经回路表达雄激素受体，并破坏雄性小鼠的雄激素水平动态减慢肠运动。该应用的目的是确定雄激素信号如何在这些肠神经系统（ENS）的神经元改变了结肠运动。对于AIM 1，我们将使用雄激素受体基因敲除小鼠以确定输入神经元中雄激素信号传导的程度可调节结肠运动。对于AIM 2，我们将确定性腺雄激素的损失如何改变肠神经元在结肠中的神经源性运动模式。这项工作的总体理由是确定 ENS中的雄激素信号传导将阐明激素如何定义改变消化健康。研究提出的是将IBS临床研究中的纠正措施转化为的重要下一步对定义循环雄激素如何定义的病理生理理解可能会导致胃肠道不适。这项工作的发现不仅会提高对胃肠道运动的基本理解，而且还揭示了靶向雄激素信号通路的治疗潜力是一种新的，更有效和个性化的治疗IBS的方法。