Wednesday, April 2, 2025
4/2/2025
Studying normal and disease processes in brain with extracellular vesicles - /// PROJECT SUMMARY Brain disorders such as psychiatric and substance use disorders are leading causes of disability worldwide. The molecular study of brain disorders remains challenging due to the lack of direct access to the diseased tissue in living patients. Extracellular vesicles (EVs) are a diverse group of nanoscale particles released by cells into the extracellular environment2. They carry a cargo of RNA, DNA, lipids, and proteins, and are critical for a variety of processes such as intercellular communication, synaptic plasticity, immune response and the disposal of cellular debris. EVs can cross the blood-brain barrier and methods are available to isolate EVs derived from brain cells from peripheral fluids such as blood. Because EVs contain a rich repertoire of biomolecules derived from their cell of origin, they have been heralded as a novel approach that provides a unique window into the disease processes in the brain and discover powerful non-invasive biomarkers that can be used to improve diagnosis, prognosis or to evaluate treatments. To the best of our knowledge there are no previous studies, as rigorous as proposed here, directly linking the RNA cargo of brain EVs isolated from serum to processes in brain. The main goal of this project is to better understand what can be learned about normal and disease processes occurring in the brain by studying brain EVs isolated from peripheral blood, and derive novel biomarkers for SZ. Tissue donors involve 16 schizophrenia (SZ) cases and 16 matched controls (CTR). For each donor, post-mortem brain tissue from the prefrontal cortex and serum is available. We will isolate three types of brain EVs from serum (BEVS), each focusing on a different class of brain cell-types. To catalogue the RNA cargo of BEVS we will generate two sequence libraries to assay a broad range of RNA species (e.g., messenger RNA, circular RNA, microRNAs, long non-coding RNA). To be able to link BEVS RNA abundance levels to processes in brain, we will perform single nucleus RNA-seq (snRNA-seq) on the brain samples to assay the cell-type specific expression of genes and transcripts. Successful completion of this project means that we have gained insight into what can be learned from normal and disease processes occurring in brain by studying BEVS isolated from peripheral blood. In addition we will have identified novel sophisticated biomarkers that eventually may be used to improve diagnosis, prognosis and treatment in the clinic.
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