Fibrosis of the Lower Esophageal Sphincter in Achalasia

贲门失弛缓症下食管括约肌纤维化

• 批准号: 10592076
• 负责人: Anand Sagar Jain
• 金额: $ 15.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592076
• 关键词: Achalasia; Apoptosis; Atropine; Biological; Biology; Biomechanics; Biometry; California; Cell Communication; Cell Culture Techniques; Cell Degranulation; Chymase; Clinical Investigator; Clinical Research; Clinical Trials; Coculture Techniques; Collagen; Data; Data Analyses; Deformity; Deglutition; Development; Digestive System Disorders; Dilatation - action; Disease; Elements; Enteral; Esophageal Diseases; Esophageal motility disorders; Esophagus; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Functional disorder; Funding; Future; Ganglia; Goals; Grant; IgE Receptors; Impairment; In Vitro; Inferior esophageal sphincter structure; Laboratories; Lead; Learning; Machine Learning; Master of Science; Measurement; Measures; Mechanics; Mediating; Medicine; Mentors; Mentorship; Molecular; Molecular Biology; Muscle; Muscle function; Myenteric Plexus; Myopathy; Natural History; Nerve Degeneration; Neurons; Nitric Oxide Donors; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Physiological; Physiology; Play; Property; Proto-Oncogene Protein c-kit; Recurrence; Relaxation; Research Personnel; Research Training; Resources; Role; Scientist; Secondary to; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Sphincter; Stains; Techniques; Testing; Time; Tissues; Training; Trichrome stain method; Tryptase; Universities; Variant; Work; career; career development; cytokine; experimental study; functional disability; imaging probe; improved; in vivo; inhibitory neuron; mast cell; medical schools; molecular targeted therapies; neuromechanism; new technology; novel; relating to nervous system; response; translational scientist

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.

项目总结/摘要 贲门失弛缓症是一种食管动力障碍，其特征是下食管括约肌开放受损 吞咽。贲门失弛缓症被认为是由神经丛中的神经节缺失引起的，神经丛支配贲门失弛缓症。 下食管括约肌尽管有很好的方法来打开下食管括约肌， 贲门失弛缓症，在贲门失弛缓症中疾病复发是常见的。因此，可能有额外的生物力学 导致贲门失弛缓症括约肌功能障碍的因素。尤其是食管下端的纤维化 括约肌可能起关键作用。本研究将从分子机制和生理机制两个方面进行探讨 肌纤维化对贲门失弛缓症影响。最近，已经确定肥大细胞活化和肥大细胞增殖是导致肥大细胞增殖的重要因素。 脱颗粒是失弛缓症的显著特征。在本提案中，我们将评估肌肉纤维化的影响， LES的生理功能（目的1）。我们将使用一种新的技术，功能性管腔成像探头 （FLIP）地形图，以进行体内实验和进行离体肌肉条记录。在目标2中， 将评估肥大细胞活化通过纤维化标志物表达和细胞凋亡引起纤维化的机制。 培养实验这项研究将有助于了解疾病的替代机制 贲门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 如分子靶向治疗。本研究还将深入了解 功能性管腔成像探头测量的精确成分。为了实现目标， 在这个赠款和他的职业目标，成为一个独立的临床和翻译研究者在 在食管动力障碍领域，主要研究者Anand Jain博士将需要接受以下方面的深入培训： 基础和先进的生物实验室技术用于研究平滑肌，食管， 功能数据分析和生物统计学。他的职业发展得到了他坚强的热情支持 导师团队，由R 01资助的肠神经元生物学家Shanthi Srinivasan博士在埃默里大学领导，包括 R 01资助的食管转化食管生理学家Ravinder Mittal博士，来自加州大学 圣地亚哥通过埃默里大学医学院提供强大的培训资源， 埃默里大学医学系和医学部提供的时间和实物支持 消化系统疾病将促进他转变为一个独立的临床科学家。