Spatial Molecular Imaging of the Human PWS Hypothalamus

Funding Summary

Dr. Yosten is using a combined spatial imaging approach to perform a detailed analysis of the proteins and genes found in hypothalamus of individuals with PWS, in comparison to typical individuals. They will build a data-sharing platform that can be used by the entire scientific community to analyze gene and protein differences in PWS brain samples. 

Lay Abstract

PROJECT SUMMARY: The goal of this project is to develop a new tool that can be used by the PWS research community to better understand the way neuropeptides interact in the brains of people with Prader Willi Syndrome. To accomplish this goal, we have obtained brain tissues from donors with PWS and matched donors without PWS (similar BMI, sex, age, race). Thus far, we have obtained brain tissues from 12 donors with PWS, and from 10 donors without PWS, but plan to request additional tissues so that we can analyze at least 15 donor samples from each group. In the first Aim, we will use these tissues to perform an innovative technique call "spatial molecular imaging (SMI)," which allows for the assessment of up to 72 proteins in tissues at the same time, and in that way develop "maps" of the tissues so that analyses of the cellular "neighborhood" can be performed. In particular,  we will assess proteins and their precursors that are known to play a role in appetite regulation, endocrine function, and metabolism, which are often dysregulated in PWS. We have already begun using SMI to evaluate gene expression of the tissues from PWS and non-PWS donors; thus, the data from this project will complement our ongoing studies. In the second Aim, we will develop and implement a novel strategy for sharing the data collected through this proposal (proteins) and our ongoing studies (gene expression) with the entire scientific community. The successful completion of this project will therefore provide the PWS research community with a novel tool that can be used to develop new and innovative hypotheses that will accelerate identification of new therapeutic targets for PWS patients.
IMPORTANCE OF THE RESEARCH: Through discussions with members of the PWS research community at the annual FPWR scientific conference, we noticed the consistent theme of a lack of sufficient information on neuropeptides and their processing as a major gap in knowledge that poses a significant hurdle towards progress in the field. The proposed research would fill this gap not only through providing critical information on peptide/protein production and processing in tissues from human PWS donors, but also by doing so in a spatially-relevant way.  
EXPECTED IMPACT AND NEXT STEPS: In the short term, this project will yield an innovative tool that can be used freely by the entire PWS research community to evaluate how the expression of genes and the proteins they encode are affected in the brains of people with PWS compared to people who are similar demographically but do not have PWS. Importantly, the proposed resource that will be generated will be expandable; thus, as new data is collected, it can be added to the tool. In the long term, we anticipate that the proposed research will lead to a greater understanding of how loss of the PWS genes impacts the molecular biology of brain.
THERAPEUTIC DEVELOPMENT: These proposed studies will lay the critical foundation for future studies designed to determine the therapeutic potential of the proteins and genes found to be altered in these experiments by provided all PWS scientists with access to this data.