Gastroesophageal reflux disease (GERD) occurs as either esophageal-GERD (E-GERD) or supraesophageal- GERD (SE-GERD). The primary cause of E-GERD is inappropriate gastro-esophageal reflux (GER), but the primary cause of SE-GERD is inappropriate gastro-esophago-pharyngeal reflux (GEPR). While there has been much investigation of the mechanisms of GER very little is known about the mechanisms of esophago- pharyngeal reflux (EPR).
The aim of this project is to determine the physiology of reflexes associated with flow across the pharyngo-esophageal junction (PEJ). We address a number of important observations in humans related to the physiology and pathophysiology of the PEJ. It has been observed that transient relaxation of the upper esophageal sphincter (TUESR) occurs with transient relaxation of the lower esophageal sphincter (TLESR), but the mechanism of this relationship is unknown. We will define the relationship between these reflexes. Distension of the esophagus causes the UES to expand to include the adjacent esophagus, but the full extent of this response and mechanism of its initiation are unknown. We will fully characterize this response and determine its neural mechanisms. In some patients with SE-GERD, the contractile response of the UES to infusion of fluid into the esophagus sometimes rapidly and briefly gives way to allow EPR, but the mechanisms of this effect are unknown. We will test the hypothesis that this rapid brief relaxation of the UES is due to activation of the esophago-UES relaxation reflex (EURR) that inhibits the esophago-UES contractile reflex (EUCR). In addition, we will determine the location along the length of the esophagus of the receptors that activate EURR. Although the neural control of GER has received much attention, the peripheral and central mechanisms of EPR are largely unknown. A newly appreciated innervation important to the function of the PEJ is the SLN afferents from the proximal cervical esophagus, but the function of these afferents is largely unknown. We will fully investigate the role of these afferents in the control of reflexes associated with anterograde and retrograde flow across the PEJ. Many of the central nervous system nuclei controlling aspects of GER, e.g. TLESR, have been identified but the central nervous system control of EPR is largely unknown. Therefore, we will investigate the role of the brainstem in controlling both EPR and GEPR. These studies will provide a firm scientific basis for defining the physiology of reflexes controlling anterograde and retrograde flow across the PEJ.

Public Health Relevance

GERD affects 10% of the US population. The primary cause of E-GERD is inappropriate GER, but the primary cause of SE-GERD is inappropriate EPR. While there has been much investigation of the mechanisms of GER, very little is known about the mechanisms of EPR. The primary barrier to EPR is the PEJ, and these studies are designed to investigate the physiology of the PEJ.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK068051-06
Application #
8742111
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J1))
Project Start
Project End
Budget Start
2014-08-11
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
$308,177
Indirect Cost
$100,436
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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