Title of project

Identifying transcriptional signatures indicative of molecular functions underlying obesity downstream of leptin

Abstract

Obesity is a trait that has received major attention given its substantial number of comorbidities. Model organisms and human studies have identified numerous molecular underpinnings, especially biological processes in the brain, however, due to the inaccessibility and molecular heterogeneity, the identification of cell population-specific molecular pathways and etiology genes has been lacking. Importantly, recent advances using in vitro modeling of human hypothalamic cells, single-cell sequencing, and high-throughput CRISPR interference (CRISPRi) screening (also referred to as ‘Perturb-seq’), have enabled screening of hundreds of genes for their causal roles in specific molecular pathways. A hypothalamic pathway with particular relevance in obesity is leptin signaling, where cell type heterogeneity has hindered advances and potential therapeutic applications for decades.

The overarching aim of my thesis is to apply CRISPRi Perturb-seq on human hypothalamic cells. The thesis will be conducted in the Pers group, at the Center for Basic Metabolic Research (CBMR) and include collaborations with researchers at the Broad Institute of Harvard and MIT (Cambridge, USA) – the institute where Perturb-seq has been pioneered – and the Kirkeby group, the group that recently, in close collaboration with the Pers group, made the first comprehensive protocol, to develop specific human hypothalamic-like cells in the dish, available. Apart from allowing me to mature into a cardiometabolic researcher, and gain proficiency in bespoke techniques (several of which I already have been acquainted with), a key output of the PhD is the identification of etiologic genes regulating leptin action across relevant hypothalamic cell populations in relation to obesity.