NEUROGLIOSOLVE · RNA biology and neuroglial function: resolving the cellular and subcellular transcriptome in myotonic dystrophy brains, towards new brain gene therapy

Линиите свързват координатора с партньорите.

Накратко на български

Цел на проекта

RNA biology is critical for the molecular orchestration of the interplay between specialized brain cell types, and disrupted RNA processing, can cause human disease. A prime example is Myotonic Dystrophy type 1(DM1), a multisystemic disorder caused by the expansion of a non-coding trinucleotide DNA repeat and that involves cognitive impairment and behavioral changes. Molecular pathogenesis is driven by the nuclear accumulation of RNA foci, which sequester RNA-binding proteins that regulate splicing, polyadenylation and subcellular localization of downstream transcripts. However, we do not know the cell populations, molecular pathways and cell-cell interactions primarily affected in the brain. A critical question to develop effective molecular therapies. My host laboratory developed a unique mouse model of DM1 that mirrors the spatiotemporal expression of toxic RNA and relevant brain phenotypes. Using these mice, I will fill three knowledge gaps:(1) I will employ advanced spatial transcriptomics to unravel the vulnerability of diverse cell types throughout brain development and aging;(2) I will use the TRAP technology to uncover subcellular transcriptomic abnormalities in specialized neuron-astrocyte contacts and identify pivotal disease intermediates of neuroglial miscommunication;(3) I will use my expertise in AAV-mediated brain gene delivery to test the capacity of engineered protein decoys, developed in my host laboratory, to release the RNA-binding proteins sequestered in brain cells and correct the behavioral, molecular neurobiological deficit in DM1 mice. Through the integration of cutting-edge transcriptomics with a new focus on synaptic neuroglial communication, I will elucidate DM1 brain pathogenesis with unprecedented spatiotemporal resolution, and offer a framework to understand other conditions mediated by toxic RNA repeats, for which DM1 serves as a paradigm. Simultaneously, my project will enhance our understanding of RNA biology in the brain.

Оригинален текст от CORDIS (на английски).

Участници

• INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция
• SORBONNE UNIVERSITE · ParisФранция

Връзки

• Виж в CORDIS
• DOI: 10.3030/101154576
• https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e522adda76&appId=PPGMS