Exploring the role of kynurenine 3-monooxygenase in microglial physiology
Lead Research Organisation:
University of Leicester
Department Name: Genetics
Abstract
Kynurenine 3-monooxygenase (KMO) is a key regulatory enzyme in the kynurenine pathway of tryptophan degradation and a promising candidate therapeutic target for several neurodegenerative disorders. In the central nervous system KMO is exclusively expressed in microglial cells where it regulates levels of kynurenic acid (KYNA), which acts as a neuroprotective metabolite by blocking excitotoxicity via antagonism of NMDA receptors. Inhibition of KMO leads to increased levels of KYNA, which ameliorates disease phenotypes in yeast, fruit fly, and mouse models of neurodegenerative disorders such as Huntington's, Parkinson's and Alzheimer's
diseases. Intriguingly, decreased KMO activity and increased levels of KYNA have also been associated with the pathophysiology of schizophrenia spectrum disorders (SSD). Notably, metabolic flux through the kynurenine pathway, and KMO activity, are increased upon immune stimulation. However, aside from its catalytic activity in the kynurenine pathway, the cellular and inflammatory roles of KMO are poorly understood, as are its effects upon KYNA-related stress responses. Here we propose to study the effects of modulating KMO activity and KYNA levels in stimulated and unstimulated microglia. KMO will be inhibited genetically or pharmacologically, and the downstream effects of these manipulations assessed. Mass spectrometry-based identification of KMO interactors and global gene expression analysis will also be performed to gain a better understanding of KMO function. In total, this work will provide insight into the role of KMO and KYNA in microglial physiology, which may ultimately inform the contribution of these players in pathological scenarios.
diseases. Intriguingly, decreased KMO activity and increased levels of KYNA have also been associated with the pathophysiology of schizophrenia spectrum disorders (SSD). Notably, metabolic flux through the kynurenine pathway, and KMO activity, are increased upon immune stimulation. However, aside from its catalytic activity in the kynurenine pathway, the cellular and inflammatory roles of KMO are poorly understood, as are its effects upon KYNA-related stress responses. Here we propose to study the effects of modulating KMO activity and KYNA levels in stimulated and unstimulated microglia. KMO will be inhibited genetically or pharmacologically, and the downstream effects of these manipulations assessed. Mass spectrometry-based identification of KMO interactors and global gene expression analysis will also be performed to gain a better understanding of KMO function. In total, this work will provide insight into the role of KMO and KYNA in microglial physiology, which may ultimately inform the contribution of these players in pathological scenarios.
Organisations
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M01116X/1 | 30/09/2015 | 31/03/2024 | |||
2098618 | Studentship | BB/M01116X/1 | 30/09/2018 | 29/09/2022 | Martina Esposito Soccoio |