FPWR's 2011 Projects

In 2011, FPWR is pleased to be able to support a diverse group of projects aimed at advancing our understanding of PWS at the molecular level, developing tools that can be used to accelerate research, and examining clinical issues in PWS.  The details of the projects, including a summary provided by each investigator, are available here; below is an overview.

Two of this year’s studies will address the underlying molecular biology of PWS.  It’s hard to find treatments for PWS when you’re not even sure exactly what’s going on.  Studies by Dr. Yeo (Univ Cambridge) and Dr. LaSalle (UC Davis) will focus on advancing our understanding of the structure and function of the PWS critical region on chromosome 15.  Dr. Yeo [Role of SNORD116/HBII-85 snoRNAs in PWS] will use a variety of biochemical techniques to study the so-called “snoRNAs”, small RNAs produced from the PWS region whose normal biological function is currently unknown.  By gaining an understanding what they normally do, Dr. Yeo hopes to understand the effects of snoRNA loss in PWS.  Dr. J LaSalle  [R-loop formation and chromatin decondensation at the PWS critical locus] has found that the snoRNAs localize to specific structures in the nucleus of neurons, and this location appears to be important for their function. While the snoRNAs are tiny, she’s also been focusing on a very large RNA molecule that stretches across the PWS region and forms ‘cloud-like’ structures in the nucleus.  The function of this “lncRNA” is also currently unknown, but Dr. LaSalle suggests its role is also a critical in the PWS puzzle. She will use advanced microscopy and genetic methods to understand these how these RNAs are interacting with the DNA in the critical region.     

 As in past years, a good portion of our support will go towards making new models that can be used to better understand PWS and to sort through potential therapies to identify those worth trying in people with PWS.  Supporting the development of models is an important role for FWPR, since once they are produced, they are available to be shared across the scientific community and can be used to ask a variety of questions. Dr. Jiang (Duke University) brings his expertise in PWS and Angelman syndrome (AS) to the development of a PWS mouse model that specifically deletes the entire PWS critical region in the brain at designated times during development [A PWS mouse model with brain specific ablation of snoRNA clusters from Snrpn to Ube3a].  This genetic manipulation is expected to allow the mice to survive the newborn period and may allow it to manifest the symptoms of human PWS more accurately.  Dr. Rob Nicholls will tackle the ongoing challenge of developing a good animal model of PWS by looking to a new species, the pig.  Recent advances in the available genetic tools now make pig models of disease a growing, fruitful area for the genetic disease research community.  With this support, Dr. Nicholls will initiate the development of such a model for PWS, which may offer new opportunities to understand the complexities of PWS in a species physiologically similar to humans [A pig model of PWS: a breakthrough for obesity, clinical and therapeutic studies].

Other projects focus particular aspects of the disorder, specifically hypotonia and muscle weakness  (Cohn) and the role of ghrelin in driving hunger (Wells, Ding) and interfering with sexual development (Elias).  Dr. Ron Cohn (Johns Hopkins School of Medicine) is an expert in hypotonia and studies how muscle mass is developed and maintained.  He will investigate muscle changes in PWS and explore the role of the PWS-region gene, necdin, in PWS muscle abnormalities. [Characterization of skeletal muscle abnormalities in mouse models of PWS: Functional role of necdin?].  Dr. Wells (Cardiff Univ) will use an existing PWS mouse (the IC del mouse) to investigate the role of ghrelin in driving hunger and feeding behaviors in PWS [Generating a novel model of ghrelin-null Prader-Willi syndrome].  In work that recently won an award, Dr. Wells’ group showed that this PWS mouse exhibits exaggerated food hoarding and altered reward drive towards food.  They will use genetic manipulations to determine if high levels of ghrelin drive these characteristics.  Dr. Ding (Xiamen Univ) will use a PWS mouse model (which she developed a few years ago in Dr. Francke’s lab with FPWR support) that has elevated ghrelin levels and increased food intake (but no obesity) to evaluate potential therapeutic drugs for their ability to interfere with ghrelin-driven food intake [Mechanism of hyperphagia and therapeutic interventions in mouse models for Prader-Willi syndrome].   Dr. Elias (UT Southwestern) will continue her study to determine how high levels of ghrelin might alter sexual development and metabolism [Role of Kiss1 neurons in mediating ghrelin’s effect on effect on reproduction and metabolism, year 2].

On the clinical front, Dr. Gros-Tsur and colleagues, with a second year of support from FPWR, will continue studies on their PWS population to gain an understanding of reproductive hormones over time [Longitudinal investigation of pubertal development and reproductive hormones in PWS from infancy through adulthood].  The information gained from their study will be useful in developing clinical guidelines to help individuals with PWS through puberty into adulthood.  Dr. Scott Hall is a psychologist at Stanford University who will be addressing one of the most tenacious challenges those with PWS face, skin picking.  He will use state of the art imaging and behavioral techniques to understand the underlying causes of skin picking in PWS, with the eventual goal of developing effective interventions to mitigate this aspect of the disorder [Environmental, physiological, and neural bases of skin picking in Prader-Willi syndrome]. Finally, we plan to support one more exciting clinical study, through an additional funding mechanism. We’ll provide more details on that project and our funding strategy in the next couple of weeks.

 If you’ve read this far, you’ll realize what an incredibly broad range of topics – all highly relevant to PWS - we’ve been able to support this year. We’re so appreciative of the scientists for the important work that they do, and so grateful to all who have donated and/or worked so hard to raise the funds needed to support them.