A metabolic profiling approach to human disorders of energy metabolism
Name
607333303-MIT.pdf
Description
Full printable version
Size
7.81 MB
Format
Adobe PDF
Checksum (MD5)
41d073504b03ee754bc4df233893ae2c
Author(s)
Shaham, Oded
Advisor(s)
Vamsi K. Mootha.
Date Issued
2009
Publisher
Massachusetts Institute of Technology
Abstract
The integrated network of biochemical reactions known collectively as metabolism is essential for life, and dysfunction in parts of this network causes human disease - both rare, inherited disorders and common diseases such as diabetes mellitus. The study of metabolic disease depends upon quantitative methods which are traditionally custom-tailored to a given compound. Recent advances in technologies such as mass spectrometry now enable the simultaneous measurement of a diverse metabolite collection spanning multiple biological pathways, an approach known as metabolic profiling or metabolomics. This dissertation describes the development of one such metabolic profiling system and its application to the study of two major topics in human energy metabolism: the fasting:feeding transition and mitochondrial disease. In the first study, we profile human plasma in response to glucose ingestion, detecting dozens of metabolite changes and identifying several distinct effects of insulin. Based on these observations, we propose a multivariate view of insulin sensitivity, and show that individuals at risk for developing diabetes mellitus can differ in their insulin response profile, a concept of potential value for estimating disease risk and progression. In the second study, we elucidate a metabolic signature of human mitochondrial disease that reflects substrate oxidation, biosynthesis and energy charge.
(cont.) We demonstrate that the culture media profile of a cellular disease model of mitochondrial dysfunction reflects the plasma profile of human patients, an approach that could be applicable to other diseases as well. In addition, we show that a combination of metabolites distinguishes individuals with mitochondrial disease from healthy individuals better than the currently used diagnostic markers. Our findings provide insight into human disorders of energy metabolism, and demonstrate the utility of a profiling approach for the understanding of metabolic disease.
Description
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Subjects
Harvard University--MIT Division of Health Sciences and Technology.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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