Periodic Reporting for period 1 - OxyBaby (The Inflammasome: a novel therapeutic target for the treatment of Hypoxic Brain Injury in Neonates)
Berichtszeitraum: 2020-09-01 bis 2022-08-31
OxyBaby is focussed on understanding the mechanisms of inflammation in the young brain after injury caused by a lack of oxygen, hypoxic injury. It is particularly focussed on an inflammatory complex called the inflammasome and a small molecule called microRNA-155, which can regulate gene expression. Anti-inflammatory therapies are being trialled in adult neurological diseases but very little is known about how targeting inflammation in the young brain can improve outcomes for newborns with hypoxic injuries. Approximately 25% of newborns affected by hypoxic injury develop neurological disorders including cerebral palsy and epilepsy. The only effective care used at the moment is cooling of babies in a treatment called ‘therapeutic hypothermia’, but it is not always successful. OxyBaby will investigate inflammatory pathways involving the inflammasome and microRNA-155 using models of hypoxic injury in the newborn brain. We will then try to treat the injuries by targeting these inflammatory pathways. The first model in Oxybaby is very similar to hypoxic injuries that leads to the development of cerebral palsy and the second model is similar to hypoxic injuries that lead to epilepsy. Both of these disorders are costly disabilities because of their persistence over the course of a patient’s life. There are also a number of comorbidities associated with hypoxic injuries, for example, people who suffer from epilepsy or cerebral palsy are more likely to experience anxiety and depression.
Excitingly, recent studies have shown that inhibiting the inflammasome complex and inflammatory pathways is a favourable target for the treatment of adult neurological disorders including stroke, Parkinson’s and Alzheimer’s. The overall objectives of this project are to explore the role of the inflammasome complex and microRNA-155 in the young hypoxic injured brain and to test targeting these pathways for treatment of the injuries. We hope to identify the exact timing and activation of these pathways following hypoxic injury and to then target components of the pathways to attempt to block the development of cerebral palsy/epilepsy using our preclinical models.
Conclusion of the action: Transgenic mouse models are critical for molecular interrogation of microRNA function in the injured brain. The work in Oxybaby has resulted in the development of novel transgenic mouse model that allows us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. This was invaluable in understanding the role of inflammation after hypoxic brain injury in the newborn brain. Deletion of microRNA-155 in the microglia of our transgenic mouse model reduced inflammation and improved motor function after hypoxic injury. Additionally, these transgenic mice had a reduction in the number and severity of seizures. This work will be continued in preclinical projects testing microRNA-155 inhibitors that are delivered shortly after injury for the treatment of hypoxic brain damage and neuroinflammation that can lead to epilepsy.
Oxybaby results also demonstrated that inflammasome inhibitors can have a significant effect on inflammation in the brain up to at least three days after injury in our preclinical model. This is a critical time point when perpetual inflammation is highly detrimental to newborn brain health and function. Ongoing work is confirming the beneficial effects of inflammasome inhibition on negative outcomes of hypoxic injury including poor motor function during development.
Excitingly, recent studies have shown that inhibiting the inflammasome complex and inflammatory pathways is a favourable target for the treatment of adult neurological disorders including stroke, Parkinson’s and Alzheimer’s. The overall objectives of this project are to explore the role of the inflammasome complex and microRNA-155 in the young hypoxic injured brain and to test targeting these pathways for treatment of the injuries. We hope to identify the exact timing and activation of these pathways following hypoxic injury and to then target components of the pathways to attempt to block the development of cerebral palsy/epilepsy using our preclinical models.
Conclusion of the action: Transgenic mouse models are critical for molecular interrogation of microRNA function in the injured brain. The work in Oxybaby has resulted in the development of novel transgenic mouse model that allows us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. This was invaluable in understanding the role of inflammation after hypoxic brain injury in the newborn brain. Deletion of microRNA-155 in the microglia of our transgenic mouse model reduced inflammation and improved motor function after hypoxic injury. Additionally, these transgenic mice had a reduction in the number and severity of seizures. This work will be continued in preclinical projects testing microRNA-155 inhibitors that are delivered shortly after injury for the treatment of hypoxic brain damage and neuroinflammation that can lead to epilepsy.
Oxybaby results also demonstrated that inflammasome inhibitors can have a significant effect on inflammation in the brain up to at least three days after injury in our preclinical model. This is a critical time point when perpetual inflammation is highly detrimental to newborn brain health and function. Ongoing work is confirming the beneficial effects of inflammasome inhibition on negative outcomes of hypoxic injury including poor motor function during development.
The overall scientific goals of the project were achieved. The role of the inflammasome complex and microRNA-155 in the young hypoxic injured brain was evaluated in preclinical models. Gene expression revealed the timing of inflammasome activation in both the injured and healthy sides of the newborn brain following hypoxic injury. We found that the inflammasome inhibitor was able to significantly reduce inflammation up to at least three days after injury in our preclinical model of hypoxic injury that induces injuries similar to those that lead to cerebral palsy in humans. We are currently expanding on these findings. We are encouraged by the data and anticipate findings will contribute to a high impact publication from this MSCA project in collaboration with our partners in University of Gothenburg, Sweden.
During the course of the project different opportunities arose and we developed a novel transgenic mouse model that allowed us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. Deletion of microRNA-155 in these transgenic mice suppressed inflammation, reduced seizure severity and improve motor function outcomes in the preclinical model of hypoxia induced seizures. This transgenic mouse model will guide future studies which attempt to block or prevent epilepsy development.
The work completed as a Marie Sklodowska Curie fellow has to date resulted in 1 preprint article, 2 conference talks, 2 invited institutional talks, 1 additional journal article and 1 review currently in preparation. The Marie Sklodowska Curie fellow has also secured an academic position in an Irish University, establishing their own research group and currently supervises 1 PhD and 1 Postdoctoral researcher.
During the course of the project different opportunities arose and we developed a novel transgenic mouse model that allowed us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. Deletion of microRNA-155 in these transgenic mice suppressed inflammation, reduced seizure severity and improve motor function outcomes in the preclinical model of hypoxia induced seizures. This transgenic mouse model will guide future studies which attempt to block or prevent epilepsy development.
The work completed as a Marie Sklodowska Curie fellow has to date resulted in 1 preprint article, 2 conference talks, 2 invited institutional talks, 1 additional journal article and 1 review currently in preparation. The Marie Sklodowska Curie fellow has also secured an academic position in an Irish University, establishing their own research group and currently supervises 1 PhD and 1 Postdoctoral researcher.
The work in OxyBaby has resulted in the development of a novel transgenic mouse model which allows us to analyse the role of the inflammatory microRNA (miR-155) in a discrete immune cell population of the brain called microglia. This model was invaluable in understanding the role of inflammation following hypoxic injury in the brain. We will continue to develop the model to further enhance our understanding of the nuanced role of microglia cells in epilepsy. Additionally, the model will be used in future studies in the MSCA fellow’s now independent lab exploring the role of neuroinflammation in other disorders including stroke and brain cancer. As the transgenic model has enormous potential as a research tool not just for epileptologists but also those studying other neurological disorders, development and ageing and normal brain function, this resource will be shared with collaborators and researchers that request it.
A particularly worrying aspect of hypoxic brain injury in newborns is increased risk among males and many of the current treatments are more effective in females. We are excited that the OxyBaby project found that targeting miR-155 in immune cells in the brain reduced seizure scores and improved motor function outcomes in both males and females. We will continue this work and will focus on designing a targeted microRNA-155 therapy that can be delivered shortly after hypoxic injury to patients as a strategy to help improve both short term and long-term outcomes. This has the potential to improve the quality of life patients with hypoxic brain injuries worldwide.
A particularly worrying aspect of hypoxic brain injury in newborns is increased risk among males and many of the current treatments are more effective in females. We are excited that the OxyBaby project found that targeting miR-155 in immune cells in the brain reduced seizure scores and improved motor function outcomes in both males and females. We will continue this work and will focus on designing a targeted microRNA-155 therapy that can be delivered shortly after hypoxic injury to patients as a strategy to help improve both short term and long-term outcomes. This has the potential to improve the quality of life patients with hypoxic brain injuries worldwide.