Fibrosis of the Lower Esophageal Sphincter in Achalasia

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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.