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Proteomics Studies of Environmental Effects and Systemic Gene Interactions in Disorders of Fatty Acid Beta-Oxidation

Wang, Wei (2011) Proteomics Studies of Environmental Effects and Systemic Gene Interactions in Disorders of Fatty Acid Beta-Oxidation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Fatty acid β-oxidation disorders (FAODs), the most frequent group of inborn errors of metabolism, are clinically heterogeneous and clear genotype-phenotype correlations have not been described. Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and short chain acyl-CoA dehydrogenase (SCAD) deficiency result from mutations on the ACADVL and ACADS genes, respectively. Multiple mutations have been described in both disorders. Acute symptoms are often induced by physiological stress such as fasting, but the pathophysiologic mechanism underlying disease symptoms and phenotypic heterogeneity remains unknown. The aim of this dissertation was to explore the biological changes induced by genetic mutations and the gene-gene interactions and environmental effects on these defects.Proteomic changes in SCAD and VLCAD deficient mice, as well as the changes induced by fasting in VLCAD deficiency, were measured quantitatively using a combination of proteomics techniques. Broad mitochondrial dysfunction and derangements in multiple energy metabolism related proteins were altered in SCAD deficiency, indicating a complex mechanism for development of symptoms. Overall, a pattern associated with hepatotoxicity implicated in mitochondrial dysfunction and alteration of fatty acid metabolism was identified. Affected pathways converge on disorders with neurologic symptoms, suggesting that even asymptomatic individuals with SCAD deficiency may be at risk to develop more severe symptoms. Several candidate biomarkers were suggested through Ingenuity Pathway Analysis. Numerous proteomic changes were characterized in VLCAD deficient mice in both fed and fasting states, and relevant biological pathway were identified. Fasting in both deficient and wild type animals induced alterations in several proteins. The pattern of alterations induced by fasting was different in VLCAD deficient mice from that in wild type animals. Mitochondrial chaperonins HSP60 and HSP10 altered differently in VLCAD deficient mice depending on the feeding state. Fasting altered an apparent compensatory increase in oxidative phosphorylation seen in the fed state. Thus, environmental factors and gene-environment interaction play important roles in the pathogenesis of VLCAD deficiency. The diversity of protein changes in variable pathways due to deficiencies in SCAD and VLCAD may help explain the phenotypic heterogeneity in patients.These proteomic studies present new paradigm for exploring the mechanisms of disease, gene-environment interactions, and their contribution to gene-gene interactions in FAODs, one group of the mandatory target diseases in newborn screening program. The results advanced the knowledge about FAODs and offered the benefits for the improvement in the diagnosis and treatment of theses disorders of great public health interest. Future characterization of functionally interactive genes and association studies in humans will provide further insight into disease mechanism. Further studies on candidate biomarkers are necessary to identify novel markers for prognosis prediction, adjunct diagnosis and therapy guidance in patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wang, Weiangei1998@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVockley, Jerryvockleyg@upmc.eduGEV1
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberFinegold, Daviddnf@pitt.eduDNF
Committee MemberBarmada, Michaelbarmada@pitt.eduBARMADA
Committee MemberFerrell, Robertrferrell@pitt.eduRFERRELL
Date: 23 September 2011
Date Type: Completion
Defense Date: 25 July 2011
Approval Date: 23 September 2011
Submission Date: 24 July 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: environmental effects; fatty acid beta-oxidation disorders; gene interactions; proteomics
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07242011-140146/, etd-07242011-140146
Date Deposited: 10 Nov 2011 19:53
Last Modified: 19 Dec 2016 14:36
URI: http://d-scholarship.pitt.edu/id/eprint/8576

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