The Molecular Mechanisms of rhIGF1 in the Treatment of Rett Syndrome and Related Disorders: Studies in Patients, Mouse and Cellular Models
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Shovlin, Stephen, The Molecular Mechanisms of rhIGF1 in the Treatment of Rett Syndrome and Related Disorders: Studies in Patients, Mouse and Cellular Models, Trinity College Dublin.School of Medicine, 2022Download Item:
Abstract:
Recombinant human Insulin-like Growth Factor 1 (rhIGF1) is an approved treatment for growth failure and IGF1 deficiency. IGF1 has multiple functions in the body including growth, cell survival, metabolism, ageing and neurodevelopment. The neuroprotective effects of rhIGF1 and its metabolite glycine-proline-glutamate (GPE), has led to a number of related clinical trials in neuropsychiatric disorders, including Rett Syndrome (RTT). RTT is a devastating X-linked neurodevelopmental disorder strongly associated with mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. Patients with RTT generally have neuro-typical development up until 6 to 18 months of age, followed by the onset of symptoms and developmental regression. Patients display a wide variety of symptoms, including; severe cognitive impairment, motor dysfunction, cardiorespiratory abnormalities, impaired gait, and repetitive hand stereotypies. The X-linked nature of MECP2 means that the presentation is more severe in males, usually leaving them non-viable, hence the vast majority of patients are female. Mutation of Mecp2 in mouse models result in phenotypes that recapitulate many of the features of RTT.
This thesis aims to understand the molecular mechanisms of rhIGF1 treatment in the context of RTT. In Chapter I, we assessed the gene expression data of whole blood samples from patients with RTT in a phase I clinical trial. This analysis revealed different transcriptional profiles of gene expression depending on whether patients showed response to treatment, as measured by the improvement to apnoeic index. This analysis highlighted the importance of IGF signaling and regulation, immune modulation, and cell cycle progression in response to treatment.
In Chapter II, Mecp2-/+ and Mecp2-/y mice were treated with rhIGF1. Locomotor activity and gene expression of the cerebellum and blood was measured to determine the effects of treatment. In Mecp2-/+ mice, rhIGF1 affected Central Nervous System (CNS) specific functions, while in Mecp2-/y mice, rhIGF1 resulted in changes in cellular and metabolic processes. We analysed locomotor and gene expression of Mecp2-/+ mice, while a colleague Albert Sanfeliu Bosch, provided sequencing data for the Mecp2-/y mice.
In the final chapter we performed in vitro experiments in neuronally differentiated SH-SY5Y cell line to identify the mechanism of action of rhIGF1 and its tripeptide GPE. Despite rhIGF1 and GPE being strongly interconnected, these drugs elicited different effects on canonical downstream signalling pathways of IGF1, including PI3K-AKT and MAPK signaling.
In this way we will examine mechanisms of rhIGF1 in RTT patients, Mecp2 mouse model and a cellular model, making use the advantages of each system in the context of RTT.
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HEA COVID Extension Fund
Higher Education Authority (HEA)
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:SHOVLISTDescription:
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Author: Shovlin, Stephen
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Tropea, DanielaPublisher:
Trinity College Dublin. School of Medicine. Discipline of PsychiatryType of material:
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