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Title page for ETD etd-07222014-114609


Type of Document Dissertation
Author Umunakwe, Obinna C.
Author's Email Address o.umunakwe@vanderbilt.edu
URN etd-07222014-114609
Title A Mechanism for Altered Polyunsaturated Fatty Acid Biosynthesis in Cystic Fibrosis
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Larry L. Swift Committee Chair
Adam C. Seegmiller Committee Member
Michael Laposata Committee Member
P. Anthony Weil Committee Member
Timothy S. Blackwell Committee Member
W. Gray Jerome Committee Member
Keywords
  • desaturase
  • arachidonic acid
  • linoleic acid
  • AMP-activated protein kinase
Date of Defense 2014-07-18
Availability unrestricted
Abstract
Cystic fibrosis (CF) is a debilitating, multi-organ, autosomal recessive disease caused by mutations leading to absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) in epithelial cells. Chronic pulmonary disease, characterized by excessive inflammation and recurrent infections, is the primary source of morbidity and mortality in individuals with CF. Altered polyunsaturated fatty acid (PUFA) biosynthesis, resulting in increased metabolism of linoleic acid (LA) to arachidonic acid (AA), plays a key role in CF pathophysiology. Increased AA biosynthesis contributes to excessive inflammation in the lungs of individuals with CF. The mechanism by which absence of functional CFTR leads to aberrant PUFA biosynthesis has been elusive. This dissertation is the first delineation of a pathway linking PUFA metabolism to CFTR. Through studies in human bronchial epithelial cells, this dissertation demonstrates that absence of functional CFTR leads to increased activation of AMP-activated protein kinase (AMPK) by calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ). Elevated AMPK activity leads to increased expression and activity of Δ6-desaturase (Δ6D) and Δ5-desaturase (Δ5D). Increased activity of Δ6D and Δ5D results in increased metabolism of LA to AA.
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