Document Details

Document Type:   Dissertation
Title:   Genetic and Environmental Factors Suggest that Dietary Fatty Acid Content, Lipid Metabolism, and Bone Properties are Key Regulators of Myeloid Progenitor Cell Frequency
Author:   Melinda E. Varney
College:   Joan C. Edwards School of Medicine
Degree Program:   Biomedical Sciences, Ph.D.
Degree:   Doctor of Philosophy
Committee Director:   Vincent E. Sollars
Document Availability:   Document available for World-Wide access.
Date of Defense:   December 2010

Acute myelogenous leukemia (AML) and its precursors are the result of the dysregulation of hematopoiesis. Hematopoiesis proceeds in a stepwise manner, beginning with hematopoietic stem cells, continuing to develop into various stages of progenitor cells, and finally becoming fully functional blood cells. As this process goes awry, immature, functionless cells of the myeloid lineage proliferate out of control. Discerning how myeloid progenitor frequency is regulated allows for a better understanding of how the process may lose control. Hematopoiesis has been shown to depend on genetic and environmental factors. In this work, I have added to this knowledge base by providing novel information about genetic and environmental components for the regulation of blood cell development. By performing colony forming cell (CFC) assays to determine myeloid progenitor cell frequency in 27 strains of mice, and using bioinformatics capabilities in the form on SNP-based in silico mapping, I have found patterns among genes located in chromosomal loci of interest for regulating this phenotype. These patterns suggest that lipid metabolism, insulin sensitivity, and bone properties are key regulators of myelopoiesis. Additionally, I have found that polyunsaturated fatty acid (FA) content in the diet is a key environmental regulator. Mice fed diets rich in omega-3 FAs have significantly lower middle and late stage progenitor cell frequency and increased common myeloid progenitor frequency over those fed more similarly to the Western diet. Collectively these data suggest that the content of diet, how it is metabolized by the body, and how this affects the bone, regulates the frequency of myeloid progenitor cells. Further research into these processes may provide novel biomarkers for disease progression and improved therapeutic options for AML  

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