Dr Florian Merkle
Laboratory Location: Anne McLaren Laboratory for Regenerative Medicine
Departmental Affiliation: WT-MRC Institute of Metabolic Science
My laboratory uses pluripotent stem cells to model human diseases with the aim of illuminating the processes that lead to disease. We are focused on diseases of the nervous system, particularly those that arise from the loss of aberrant function of neurons in the hypothalamus, an evolutionarily ancient brain region that regulates essential physiological and behavioural processes. In particular, obesity is thought to result from abnormal function of hypothalamic neurons that regulate food intake, and the sleep disorder obesity results from the specific loss of sleep-regulatory hypothalamic neurones. I recently developed methods to generate these hypothalamic neurone populations from human pluripotent stem cells, and edit their genomes to generate reporter cell lines and to introduce disease-causing mutations. We are combining these tools to pursue two research questions:
1) Cellular mechanisms of aberrant feeding regulation
Many mutations that cause obesity are known, but the mechanisms by which they cause disease are poorly understood. We are using genetic and pharmacological approaches to test the hypothesis that certain mutations cause obesity by affecting the function of hypothalamic neurones that regulate feeding behaviour. This work is being carried out in collaboration with Prof. Sir Steve O’Rahilly and Prof. Sadaf Farooqi at the Institute of Metabolic Science at the University of Cambridge.
2) Role of DNA methylation in neuronal health and degeneration
Normal DNA methylation is essential for proper development and cellular function. Specific point mutations in the DNA methyltransferase DNMT1 lead to progressive neurodegenerative diseases, one of which is characterised by early-onset narcolepsy. The mechanism by which aberrant methylation leads to the loss of specific neurone types is being pursued biochemically and in genome-edited stem cells and mouse models.
I am interested in how human genetic variation contributes to disease, in particular obesity and sleep disorders. These diseases are due to the loss or dysfunction of particular types of neurons (brain cells) found in a region of the brain known as the hypothalamus. Hypothalamic neurons can be generated in a culture dish from human stem cells. Our laboratory uses a combination of cutting-edge approaches to determine how disease associated genes lead to disease states at the level of cells (in human stem cell-derived neurons) and organisms (in gene edited mice).
Outstanding graduate students or postdoctoral candidates interested in joining our team are encouraged to write me directly at firstname.lastname@example.org.