New molecular understanding of mental disorders through deep cerebrospinal fluid phenotyping

Descripción del proyecto

Biomarcadores moleculares de los trastornos mentales

Los trastornos mentales, como la depresión, la esquizofrenia y el trastorno bipolar, son complejos y multifactoriales, y en ellos intervienen factores genéticos y ambientales que repercuten en la función encefálica y el comportamiento. Sin embargo, la falta de una visión mecánica y de biomarcadores moleculares dificulta el diseño de tratamientos eficaces. El equipo del proyecto Deep-CSF-inPsych, financiado por el Consejo Europeo de Investigación, pretende transformar este campo mediante el fenotipado profundo del líquido cefalorraquídeo (LCR) en muestras de personas con trastornos psicóticos de primer episodio, depresión y controles sanos. Utilizando tecnologías ómicas de vanguardia, el estudio se centrará en metabolitos y proteínas del LCR pertinentes para la enfermedad. Mediante un enfoque de biología de sistemas, el equipo de investigación analizará las vías biológicas y los mecanismos moleculares de los trastornos psiquiátricos, lo que permitirá identificar nuevas dianas terapéuticas y avanzar en las estrategias de tratamiento de la salud mental.

Objetivo

Psychiatry is lacking truly objective markers and the limited molecular understanding of disease mechanism underlying mental disorders inhibits us to design new therapies, for which identification of novel treatment targets are urgently needed. No study has yet conducted deep phenotyping of the cerebrospinal fluid (CSF), which is the biological material closest to the brain that is assessable for direct investigations in intra vitam, and no large longitudinal CSF studies on mental disorders currently exists.

I aim at a paradigm change by advancing the current state-of-the-art through novel deep CSF phenotyping on unique CSF samples from individuals with first episode psychotic disorders, depression and healthy controls, to be followed-up longitudinally clinically, and in nationwide registers. Pushing the frontiers of knowledge within psychiatry, I will use novel technologies and for the first-time for these disorders use cutting edge single cell sequencing of cell compartments in the CSF potentially involved in or affected by disease, with a particular focus on T cell alterations. For the first time, longitudinal omics analyses will be conducted with targeted and untargeted metabolomics and proteomics to identify disease relevant metabolites and proteins in the CSF, increasing the understanding of molecular mechanisms of psychiatric symptoms and diagnosis. Systems biology and deep learning approaches will provide crucial insights into biological pathways and the interplay between brain pathophysiological mechanisms in a cross-diagnostic manner, potentially identifying biologically distinct clusters, disentangling the involved molecular mechanisms.

This approach is unprecedented. Identification of novel therapeutic targets, increasing the understanding of mental disorders and insights to molecular mechanisms through deep CSF phenotyping has a ground-breaking potential for psychiatry and neuroscience - paving the way for more effective and mechanism-based treatment.