NMR based metabolomics is a powerful tool for studying metabolic changes that underlie neurodegeneration. However, to maximise this information the compartmentation of metabolites must also be understood. We will develop High Resolution Magic Angle Spinning (HRMAS) NMR spectroscopy as a tool for obtaining metabolic fingerprints from neuronal tissue that reflect such compartmentation. Integration of this metabolomic data together with transcriptional and histopathological data will provide a powerful means for generating and testing hypothesis of neurodegenerative pathogenesis. Our studies will focus upon the neuronal ceroid lipofuscinoses (NCLs) or Batten disease, a group of fatal neurodegenerative disorders. We have chosen this set of diseases as genetically accurate mouse models for these monogenetic autosomal recessive disorders exist, although the underlying disease mechanisms remain poorly understood. Pathological data of selective neuronal loss and glial activation during disease progression now exist and these disorders represent an ideal test-bed for developing an integrated metabolomic approach for exploring neurodegenerative mechanisms. Our working hypothesis is that detailed knowledge of the events that accompany disease at a transcriptional, metabolic and histological level will allow the development of a robust HRMAS tool for metabolic fingerprinting, which will not only reflect metabolite changes but also monitor cellular compartmentation. To investigate this we have four specific aims: i. To correlate changes in NMR observable metabolites with perturbations in metabolic pathways identified using mass spectrometry; ii. To correlate the NMR observable metabolites with metabolic compartmentation between cell types and within cell organelles. iii. To correlate NMR observable metabolites with histopathological data; iv. To correlate NMR observable metabolite changes with transcriptional changes. Our data will provide proof-of principle for this methodology, and establish a means for exploring other neurolodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21DK070288-02S1
Application #
7281834
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Castle, Arthur
Project Start
2005-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$104,866
Indirect Cost
Name
University of Cambridge
Department
Type
DUNS #
226552610
City
Cambridge
State
Country
United Kingdom
Zip Code
CB2 1-TN
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