Fibrosis of the Lower Esophageal Sphincter in Achalasia

项目摘要/摘要 失弛缓症是一种以下食道括约肌开放受损为特征的食道动力障碍。 带着吞咽。失弛缓症被认为是由神经丛中的神经节丢失引起的，神经丛 下食道括约肌。尽管切开下食道括约肌的方法很好 失弛缓症，疾病复发在失弛缓症中很常见。因此，可能存在额外的生物力学 导致贲门失弛缓症括约肌功能障碍的因素。尤其是下段食道的纤维化 括约肌可能起到关键作用。本研究将从分子机制和生理机制两方面进行研究。 肌肉纤维化对失弛缓症的影响。最近发现，肥大细胞激活和 脱颗粒是贲门失弛缓症的一个显著特征。在这项提案中，我们将评估肌肉纤维化的影响 关于LES的生理功能(目标1)。我们将使用一种新技术，功能性管腔成像探头 (翻转)地形图，用于进行活体实验和进行体外肌肉条记录。在目标2中，我们 将通过纤维化标志物的表达和细胞来评估肥大细胞激活在导致纤维化中的机制 培养实验。这项研究将有助于理解疾病的替代机制。 失弛缓症的发病机制和功能损害。最终，这可能会导致新的治疗方法 在失弛缓症等方面的分子靶向治疗。这项研究也将有助于深入了解 功能管腔成像探头测量的精密组件。为了实现所提出的目标 第四，他的职业目标是成为一名独立的临床和翻译研究人员 在食道动力障碍领域，首席调查员Anand Jain博士将需要在以下方面进行深入培训 用于研究食道平滑肌的基础和高级生物实验室技术 功能数据分析和生物统计学。他的事业发展得到了他强大的支持 导师团队，由埃默里大学R01资助的肠神经生物学家Shanthi Srinivesan博士领导，包括 R01资助加州大学食道翻译生理学家Ravinder Mittal博士 圣地亚哥。通过埃默里大学医学院提供的强大培训资源和受保护 时间和实物支持由埃默里大学医学系和 消化系统疾病将帮助他转变为一名独立的临床科学家。

Project Summary / Abstract Achalasia is an esophageal motility disorder characterized by impaired lower esophageal sphincter opening with swallowing. Achalasia is thought to be caused by ganglion loss in the neural plexus that innervates the lower esophageal sphincter muscle. Despite excellent approaches to open the lower esophageal sphincter in achalasia, disease recurrence in achalasia is common. As such, it may be there are additional biomechanical elements that cause sphincter dysfunction in achalasia. In particular the fibrosis of the lower esophageal sphincter muscle may play a critical role. This proposal will study the molecular mechanism and physiological impact of muscle fibrosis in achalasia. Recently, it has been identified that mast cell activation and degranulation is a prominent feature in achalasia. In this proposal, we will assess the impact of muscle fibrosis on physiological function of the LES (Aim 1). We will use a novel technology, functional lumen imaging probe (FLIP) topography, to conduct in vivo experiments and perform ex vivo muscle strip recordings. In Aim 2, we will assess the mechanism of mast cell activation in causing fibrosis via fibrosis marker expression and cell culture experiments. This study will facilitate an understanding of the alternative mechanisms of disease pathogenesis and functional impairment in achalasia. Ultimately this may lead to novel treatment approaches in achalasia such as molecularly targeted therapy. This study will also provide an in-depth understanding of the precise components measured by the functional lumen imaging probe. In order to accomplish the aims put forth in this grant and his career goal as becoming an independent clinical and translational investigator in the field of esophageal motility disorders, the Principle Investigator, Dr. Anand Jain, will require in-depth training in both fundamental and advanced biological laboratory techniques used to study smooth muscle, esophageal functional data analysis, and biostatistics. His career development is enthusiastically supported by his strong mentorship team, led by R01-funded enteric neuronal biologist Dr. Shanthi Srinivasan at Emory and including R01-funded esophageal translational esophageal physiologist Dr. Ravinder Mittal from University of California San Diego. The robust training resources available via the Emory University School of Medicine and protected time and in kind support provided by the Emory University Department of Medicine and the Division of Digestive Diseases will facilitate his transformation to an independent clinician scientist.