Neurons rely on RNA-binding proteins to assemble into dynamic clusters that control when and where genes are switched on in the brain. These clusters form through flexible, disordered regions of the proteins that bind multiple RNA molecules at once, creating a finely tuned system for processing genetic instructions. The problem is that mutations in these proteins disrupt the clusters in ways that are poorly understood, and many brain disorders linked to these mutations currently have no effective treatments. This project will map how the clusters assemble in cortical neurons, identify the sequence codes that determine which RNAs are affected by specific mutations, and then use that knowledge to build synthetic genetic modules that can sense their own context and switch therapeutic genes on only where and when they are needed. If successful, the work could lead to a new class of "auto-gating" gene therapies for brain disorders—treatments that activate themselves in the right cells at the right time, reducing side effects and improving precision. The research is primarily fundamental science, but understanding how cells naturally regulate RNA in space and time is a prerequisite for designing therapies that mimic that control.
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Neuronal gene regulation is spatiotemporally controlled in a highly context- dependent manner through combinatorial interactions of RNA binding proteins (RBPs). These interactions are typically mediated by the intrinsically disordered domains (IDRs) of RBPs and their multivalent binding to RNA. A key goal of biomedical research is to determine how multivalent assemblies of RBPs on primary transcripts enable selective and developmentally dynamic regulatory programmes, and how these programmes are disrupted in pathological contexts. A closely related goal is to exploit knowledge of these mechanisms to establish improved therapeutics for brain disorders that currently lack effective treatments. We will draw on our collective extensive expertise in the areas of RNA biology, genomics, and brain disorders, to: (a) understand mechanisms underlying the formation of ribonucleoprotein (RNP) assemblies that are critical for the spatiotemporal regulation of RNA processing and translation in cortical neurons; (b) systematically dissect mechanisms whereby mutations in brain disorder-relevant RBPs selectively perturb RNP assembly and function, and define the underlying sequence codes mediating this selectivity; and (c) develop combined transcriptional, RNA processing and localization modules for autonomously-gated gene therapeutic applications. Thus, through a new understanding of post-transcriptional gene regulation, we will develop context-dependent therapeutic strategies for brain disorders.
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