Patient-specific hypothalamic neurons to elucidate human obesity
Obesity arguably accounts for the greatest proportion of illness, incapacity, and societal cost of any single health problem in the U.S. Upwards of 60% of risk variance for obesity is genetically conveyed. And the majority of the known obesity-related genes are expressed in the brain, acting in part through hypothalamic neurons affecting food intake. Access to human neuro-cellular model systems is critical to gaining insights into the molecular neurophysiology of body weight regulation in humans. The Doege lab utilizes patient-specific hypothalamic neurons to elucidate the molecular mechanisms of human monogenic obesity (e.g., melanocortin-4 receptor deficiency). These studies may ultimately lead to the development of novel therapeutic strategies for human obesity.
Our focus is on:
1) The creation of a series of human hypothalamic cell types from patient-specific induced pluripotent stem cells (iPSC).
2) The investigation of the molecular mechanisms underlying monogenic forms of obesity.
3) The identification of modifiers of monogenic obesity that reduce penetrance.
To address these questions, we employ stem cell-based approaches (monogenic obesity patient-specific iPSC, in vitro differentiation into specific subtypes of hypothalamic neurons), genome-editing tools such as CRISPR, whole-exome/genome sequencing, single-cell whole-transcriptome sequencing, cell biology and biochemical approaches.
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Andang, M., Moliner, A., Doege, C.A.
, Ibanez, C.F., and Ernfors, P. (2008) Optimized mouse ES cell culture system by suspension growth in a fully defined medium. Nat. Protoc
. 3: 1013-1017
Varlamov, O., Volchuk, A., Rahimian, V., Doege, C.A.
, Paumet, F., Eng, W.S., Arango, N., Parlati, F., Ravazzola, M., Orci, L., Söllner, T.H., and Rothman, J.E. (2004) i-SNAREs: inhibitory SNAREs that fine-tune the specificity of membrane fusion. J. Cell Biol.
Burri, L., Varlamov, O., Doege, C.A.
, Hofmann, K., Beilharz, T., Rothman, J.E., Söllner, T.H., and Lithgow, T. (2003) A SNARE required for retrograde transport to the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA
100: 9873-9877Doege, C.A.
, Kerskens, C.M., Romero, B.I., Brunecker, P., Junge-Hulsing, J., von Pannwitz, W., Muller, B., and Villringer, A. (2003) Assessment of diffusion and perfusion deficits in patients with small subcortical ischemia. Am. J. Neuroradiol
. 24: 1355-1363Doege, C.A.
, Tavakolian, R., Kerskens, C.M., Romero, B.I., Lehmann, R., Einhaupl, K.M., and Villringer, A. (2001) Perfusion and diffusion magnetic resonance imaging in human cerebral venous thrombosis. J. Neurol
. 248: 564-571Doege, C.A.
, Kerskens, C.M., Romero, B.I., Brunecker, P., Junge-Hulsing, J., Muller, B., and Villringer, A. (2000) MRI of small human stroke shows reversible diffusion changes in subcortical gray matter. Neuroreport
11: 2021-2024Please click the PubMed link below for a complete list of published work in MyBibliography:
Obesity, hypothalamus, leptin-melanocortin pathway, melanocortin-4 receptor, monogenic obesity, stem cell-based approaches, human induced pluripotent stem cells, genome-editing tool, CRISPR, in vitro differentiation, patient-specific hypothalamic neurons, precision medicine