Research Interests
The Merkle laboratory aims to uncover the mechanistic basis of common human neurological diseases and develop novel therapies using a combination of human pluripotent stem cell (hPSC)-derived culture systems and animal models. We use a variety of techniques including CRISPR/Cas9-based genome engineering, single-cell transcriptomics, high content imaging, electrophysiology and calcium imaging, and animal physiology and behaviour. Our research focuses on:
1) Cellular models of obesity and anti-obesity drug discovery
Obesity leads to millions of premature deaths each year and lacks broadly effective treatments. It has a strong genetic basis and is caused in part by the abnormal function of cell populations in the hypothalamus that regulate appetite. We generate these human hypothalamic neurons from hPSCs to take advantage of the fact that can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled. These advantages provide an unprecedented opportunity to study the genetic and environmental factors underlying obesity, and we are using the system to ask several questions:
A) how do appetite-regulatory human neurons respond to metabolites, hormones, and drugs?
B) which genes associated with obesity act in hypothalamic neurons, and how does their dysfunction alter cellular function?
C) can a combination of discovery-driven high-throughput approaches using obesity-relevant phenotypic readouts, and hypothesis-driven deep phenotyping of hypothalamic neurons reveal novel treatment strategies for obesity?
2) Shared mechanisms in metabolic and neurodegenerative disease
Mid-life obesity and diabetes has been identified as is a potential risk factor for dementia later in life, and certain anti-obesity drugs are neuroprotective. We are testing the hypothesis that there are shared mechanisms between these diseases using an aggressive scrapie in vivo model of neurodegeneration, and have found that drugs used to treat obesity and diabetes are neuroprotective. We combine detailed machine learning-assisted behavioural phenotyping with histology and multi-‘omics integration to gain insight into candidate neuroprotective mechanisms, and then test these mechanisms in different hPSC-derived cell types. Our ultimate aim is to identify safe and effective neuroprotective strategies that could slow neurodegenerative processes or reduce neurodegenerative disease risk at the population level.
I am always happy to hear from outstanding graduate and postdoctoral candidates via email.
Group Members
Cortina Chen, Postdoctoral Research Associate - cc2048 at cam.ac.uk
Diego Peretti, Visiting Researcher - dap57 at cam.ac.uk
Dmytro Shepilov, Visiting Student - ds2096 at cam.ac.uk
Ed Harding, Postdoctoral Research Associate - ech66 at cam.ac.uk
Eugene Seah, Research Laboratory Coordinator - jwes2 at cam.ac.uk
Pratik Koppikar, PhD Student (co-supervised by Michael Ward, NIH) - pratik.koppikar at nih.gov
Simone Mazzaferro, Research Associate - sm2676 at cam.ac.uk
