Exploration of the mechanisms of visceral hypersensitivity in the human gastrointestinal tract in health and disease
Lead Research Organisation:
Queen Mary University of London
Department Name: UNLISTED
Abstract
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Technical Summary
Functional Gastrointestinal Disorders (FGID) affect 9-12% of the UK population. The commonest symptom experienced by FGID patients is pain, however, the heterogeneity of the group and lack of effective clinical investigations has prevented identification of its aetiology.
Visceral hypersensitivity is the most consistent experimental finding in FGID patients and two main hypothesise regarding its mechanism exist. The first states that sensitisation of peripheral and/or central afferents develops as a result of previous inflammation or injury. The second states that aberrant processing of visceral sensation occurs within the brain as a result of psychological abnormalities.
I have investigated human brain-gut interactions using a combination of imaging techniques and have designed several models of oesophageal hypersensitivity which have utilised both psychological modulation and central/peripheral sensitisation of which I have explored pharmacologically. Based on my observations I have developed a conceptual model of the mechanisms of visceral hypersensitivity and I now wish to test the validity of this model in health and disease.
Objectives: To differentiate between the putative mechanisms of visceral hypersensitivity in patients with unexplained GI pain.
Design: Whole human studies in healthy subjects and patients with visceral hypersensitivity.
Methodology: Study 1: In healthy subjects I will use Magnetoencephalography and Cortical Evoked Potentials to investigate the effects that peripheral/central sensitisation and heightened vigilance have on the cortical regions that process the sensory discriminatory and affective/cognitive aspects of visceral pain processing. Study 2: In healthy subjects I will determine the effects of repeated acid exposure on the development and severity of oesophageal hypersensitivity. Study 3: In healthy subjects I will determine the effects of NMDA receptor blockade on the development of oesophageal hypersensitivity induced by either peripheral/central sensitisation or psychological manipulation. Study 4: In healthy subjects and patients with unexplained oesophageal pain or oesophagitis, oesophageal biopsies will be taken to look for the expression of biological markers of hypersensitivity and these findings compared to physiological measures of oesophageal sensitivity. The study will be repeated after six weeks of gastric acid suppression. Study 5: Using data obtained in my initial studies, I will test my conceptual model of visceral hypersensitivity in a cohort of patients with unexplained oesophageal pain.
Outcome: A detailed understanding of the mechanisms of visceral hypersensitivity will facilitate the development of novel treatments which specifically target the appropriate pathophysiology, resulting in benefits to the well being of patients and increased efficiency in healthcare utilisation.
Visceral hypersensitivity is the most consistent experimental finding in FGID patients and two main hypothesise regarding its mechanism exist. The first states that sensitisation of peripheral and/or central afferents develops as a result of previous inflammation or injury. The second states that aberrant processing of visceral sensation occurs within the brain as a result of psychological abnormalities.
I have investigated human brain-gut interactions using a combination of imaging techniques and have designed several models of oesophageal hypersensitivity which have utilised both psychological modulation and central/peripheral sensitisation of which I have explored pharmacologically. Based on my observations I have developed a conceptual model of the mechanisms of visceral hypersensitivity and I now wish to test the validity of this model in health and disease.
Objectives: To differentiate between the putative mechanisms of visceral hypersensitivity in patients with unexplained GI pain.
Design: Whole human studies in healthy subjects and patients with visceral hypersensitivity.
Methodology: Study 1: In healthy subjects I will use Magnetoencephalography and Cortical Evoked Potentials to investigate the effects that peripheral/central sensitisation and heightened vigilance have on the cortical regions that process the sensory discriminatory and affective/cognitive aspects of visceral pain processing. Study 2: In healthy subjects I will determine the effects of repeated acid exposure on the development and severity of oesophageal hypersensitivity. Study 3: In healthy subjects I will determine the effects of NMDA receptor blockade on the development of oesophageal hypersensitivity induced by either peripheral/central sensitisation or psychological manipulation. Study 4: In healthy subjects and patients with unexplained oesophageal pain or oesophagitis, oesophageal biopsies will be taken to look for the expression of biological markers of hypersensitivity and these findings compared to physiological measures of oesophageal sensitivity. The study will be repeated after six weeks of gastric acid suppression. Study 5: Using data obtained in my initial studies, I will test my conceptual model of visceral hypersensitivity in a cohort of patients with unexplained oesophageal pain.
Outcome: A detailed understanding of the mechanisms of visceral hypersensitivity will facilitate the development of novel treatments which specifically target the appropriate pathophysiology, resulting in benefits to the well being of patients and increased efficiency in healthcare utilisation.
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ORCID iD |
| Qasim Aziz (Principal Investigator) |