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Liquid-Liquid Phase Separation and Translational Control in the developing cortex and its implications for Neurodevelopmental Disorders.

Project description

The origins of neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) such as Fragile X syndrome are increasing in prevalence, yet their molecular origins remain unclear. Supported by the Marie Skłodowska-Curie Actions programme, the Neuro-Phase project will investigate how disruptions in liquid-liquid phase separation (LLPS), a process critical for regulating protein production, may contribute to altered brain development. Using human brain organoids and embryonic brain tissue models, Neuro-Phase will explore how early disturbances in LLPS affect neural circuit formation. By clarifying these mechanisms, the project aims to improve understanding of the early biological events leading to NDDs and to inform future therapeutic strategies.

Objective

Neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS), are a heterogeneous group of conditions leading to difficulties with speech, learning and other neurological functions greatly affecting patients and healthcare, societal, and educational systems. The rising prevalence of NDDs highlights the urgent need to understand their origins, often rooted in early cortical development. In humans, the cerebral cortex, responsible for cognitive functions like language and learning, is susceptible to disruptions during early brain development, a process tightly regulated by neuronal growth and protein synthesis. The coordination of biochemical events in eukaryotic cells, including protein synthesis, is facilitated by compartmentalizing key molecules either into organelles or as membraneless condensates via liquid-liquid phase separation (LLPS). LLPS is crucial for neurotransmission, memory, and synaptic plasticity. The fragile X messenger ribonucleoprotein 1 (FMRP) has been shown to undergo LLPS with the translation factor 4E-BP2 (eukaryotic initiation factor 4E binding protein 2), a key regulator in the mechanistic target of rapamycin (mTOR) signaling pathway implicated in both autism and FXS and the development of cortical outer radial glia. The Neuro-Phase project will investigate the role of LLPS and the molecular and cellular mechanisms involved in NDDs and more specifically the role of 4E-BP2-FMRP LLPS interaction in translational control and early human brain development which has yet to be explored. To test this hypothesis, the Neuro-Phase project will use innovative biological models, including human induced pluripotent stem cell-derived brain organoids and organotypic cultures of post-mortem human embryonic cortical explants. This project will provide critical insights into the pathogenesis of NDDs by identifying potential therapeutic targets, that leverage cellular intrinsic mechanisms like LLPS, to mitigate or prevent these conditions.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

IDRYMA TECHNOLOGIAS KAI EREVNAS
Net EU contribution

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€ 181 423,68
Address
N PLASTIRA STR 100
70 013 IRAKLEIO
Greece

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Νησιά Αιγαίου Κρήτη Ηράκλειο
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