Modelling neurodevelopmental and molecular mechanisms of human genetic obesity (360G-Wellcome-208987_Z_17_Z)

The principal goal of this proposal is to develop novel platforms to study neurodevelopmental and mechanistic causes of severe obesity. Established very early in human development, body weight regulation is brain-governed by the hypothalamus. Consequently, genetic variants acting by disrupting hypothalamic function lead to severe obesity. However, the manner in which these variants contribute to obesity via exerting neurodevelopmental and molecular changes has been difficult to study since human brain tissue is inaccessible. Historically, rodent models have extensively contributed to our understanding of energy homeostasis, but they carry inherent limitations due to inter-species differences in brain structure and physiology, as well as gene sequences. Therefore, development of human study systems for disease modelling is an important complementary approach to animal and patient studies aimed at investigating human obesity. We propose to use several novel methodologies: precise genome engineering with CRISPR/Cas9 in stem cells, 2D hypothalamic cultures, as well as 3D brain organoids, to: (1) generate physiologically relevant cellular and tissue models of human genetic obesity; (2) investigate neurodevelopmental aspects of the disease; (3) utilise the models to study molecular mechanisms leading to obesity.