Prader-Willi syndrome (PWS) is caused by a loss of expression of specific genes normally expressed only from paternal alleles on chromosome 15. PWS patients display common symptoms, which include feeding difficulties in infancy, loss of muscle tone, rapid weight gain after two years of age, extreme hunger and unrelenting appetite, obesity, and some degree of developmental delay. PWS affects specific brain regions at the cellular level in humans, making stem cell technology a particularly effective method for the study of this disease. Stem cell technologies enable researchers to generate and study the cell types affected by human diseases, creating a model of the „disease in a dish‟. In order to better understand how Prader-Willi syndrome affects cells in the brain, we will transform skin cells from PWS patients into pluripotent stem cells (iPS). Induced pluripotent stem cells can give rise to every cell type in the human body. We will differentiate the iPS cells into brain cells (neurons) characteristic of particular regions of the brain. For example, we will make neurons characteristic of the part of the brain (hypothalamus) that plays a critical role in the control of food intake. The neurons generated from PWS patients will allow us to characterize the molecular and cellular defects that are caused by this genetic syndrome. Understanding how PWS affects the brain at the cellular and molecular level can inform novel therapeutic targets for PWS patients.
RESEARCH OUTCOMES: Recently developed stem cell technologies enable researchers to generate and study the cell types affected by human diseases, creating a model of the ‘disease in a dish’. In order to better understand the central nervous system manifestations of Prader-Willi syndrome, namely hyperphagic obesity, we transformed skin cells from PWS patients into induced pluripotent stem cells (iPSC). iPSC generated from individuals with PWS were subjected to numerous tests to ensure the quality of the stem cells. We next applied chemical compounds to the stem cells in order to turn the stem cells into brain cells or neurons. Neurons generated “in a dish” from iPSC are called iPSC-derived neurons. PWS iPSC efficiently differentiated to iPSC-derived neurons and produced brain-specific proteins. Thus, we have established that iPSC and the relevant differentiated cell types, such as neurons, may be utilized to study the neuro-molecular mechanisms of PWS at the cellular level. Experiments in which we compare various aspects of iPSC-derived neurons from unaffected “control” individuals and PWS patients are ongoing. These will investigate not only biochemical differences between such neurons, but also differences in the way these cells form connections/circuits with each other. Insights into the effects of PWS on food intake (hyperphagia), obesity, growth, and behavior are among our goals.
Rudolph Leibel, MD
$54,000 (OSS Funds)