Project description

Humanized murine model for bipolar disorder and lithium response

Bipolar disorder (BD) is a highly heritable psychiatric illness, having a lifetime prevalence of 1–3%. The gold standard treatment, lithium, was identified more than 70 years ago through clinical observation without using any rational drug design. Response to lithium varies considerably among patients, with 40–50% of patients showing inadequate clinical responses and/or serious side effects. The lack ofneurobiological understanding of BD pathology and the myriad of biological effects of lithium has blockedthe improvement of current treatments and the discovery of new therapeutic targets.

One of the main challenges that has limited research advances in psychiatry is the lack of cellular, tissueor animal models representative of mental disorders. We propose to break this barrier grafting, in a neurogenic niche in rodents, olfactory neuroepithelium (ONE) neural progenitor cells derived from BD type-I patients which do or do not respond to lithium treatment. Preliminary data demonstrate that animals develop a BD-like phenotype and strikingly this phenotype is specifically reversed after chronic lithium treatment in animals grafted with ONE cells from lithium responders. Based on these results, this project will design a new animal model for BD type-I exploring the behavioral phenotype, cell identity and function of the grafted human cells and the mouse cells surrounding those using immunohistochemistry, electron microscopy, electrophysiology, chemogenetics, viral tracing and proteomics. Predictive validity and its underlying mechanisms of the therapeutic and peripheral side effects will be explored after chronic treatment with lithium and valproic acid.

Thus, this new mouse model will directly contain the genetic and epigenetic changes that take place in the human patients which will open a new window to drug discovery

and personalized medicine in psychiatry.

If you are interested in applying for MSCA-PF, please submit by email to esther.berrocoso@uca.es (no later than 30th of June 2024) the following documents:

1. CV (including complete contact details and list of publications, projects, etc., and describing academic achievements and research expertise, focusing on those aspects relevant in the context of the project).

2. Motivation letter (including information concerning your research and career interests and goals, project idea aligned with our research lines and how the candidate will contribute with his/her expertise in the project, and your interests in this call).