Identification and comprehensive structural characterization of serum lipid markers to Type 1 diabetes progression
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Ngoc H. M. Vu (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
- Advisor
- Qibin Zhang
Abstract: Type 1 diabetes (T1D) is resulted from a self-destruction of insulin-secreting pancreatic ß-cells, but the exact etiology remains unknown despite evidence indicating interaction between environmental and genetic factors. For the genetically predisposed individuals of T1D, islet autoantibodies are used for predicting the likelihood of T1D in the future, however, neither the appearance nor the titer can indicate the extent of the destruction of ß-cells or quantify the remaining ß-cell mass. Therefore, additional biomarkers are needed to monitor the health status of ß-cell and the development of T1D. Dysregulation of lipid metabolism exists in distinctive disease states. Several studies suggested lipids as a potential biomarker for T1D and the dysregulated profiles of lipids in T1D blood serum could predict the seroconversion of autoantibody positivity. However, many of the potential T1D lipid markers reported to date have not been validated in independent cohorts, and the structural identifications are ambiguous as only the total number of carbon atoms and double bonds in the fatty acyl chains were reported. There is no detailed structural information reported for the lipid species regarding the fatty acyl compositions and the location of C=C double bond- those fine structural details can determine the biological functions of lipids and help to elucidate the pathogenic mechanism of T1D. Based on these, we hypothesize that 1) lipid markers that either shed from diseased pancreatic ß-cells or as a systemic response to autoimmune attack exist in human serum; 2) dysregulation of lipid markers can predate the appearance of islet autoantibodies. Using advanced lipidomics tools and longitudinally collected sera from a well characterized T1D cohort, the primary goal of this project is to identify a panel of serum lipid markers correlated to T1D progression, with unambiguous characterization of their molecular structures. In this dissertation, we are focusing on the following aims: 1) Create a comprehensive human serum lipid library for high throughput LC-MS based lipidomics analysis; 2) Identify candidate lipid markers to T1D progression through quantitative profiling of the temporal changes of serum lipids in T1D cohorts; and 3) Comprehensively characterize the structures of the lipid markers. These aims were addressed in four projects that employed advanced instrumentation, sophisticated data analysis tools and precious human samples longitudinally collected from a T1D cohort. The first project generated a comprehensive library contains LC retention time and accurate mass of each lipid molecular species, and will be used for accurate and speedy identification of serum lipids in T1D subjects. In addition, this library can be implemented for an accurate and high throughput analysis of human serum lipids related to other diseases. The second and third project focused on development of Ozoneinduced dissociation (OzID) on a high resolution MS to determine unambiguously the C=C double bond positions in unsaturated lipids. This technique is based on a highly selective gas phase reaction between C=C and ozone. We achieved high efficiency of OzID in both direct infusion- and RPLC-based workflows to effectively elucidate C=C unsaturation in complex biological samples. Using the methodologies developed in the first three projects, the last project profiled temporal changes of lipidome in a T1D cohort, and identified a list of candidate lipid markers. These lipid markers showed a distinct profile prior to appearance of T1D as compared to healthy controls.
Identification and comprehensive structural characterization of serum lipid markers to Type 1 diabetes progression
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Created on 8/1/2019
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Additional Information
- Publication
- Dissertation
- Language: English
- Date: 2019
- Keywords
- AMT library, Human serum, Lipidomics, Ozone-induced dissociation, Type 1 diabetes
- Subjects
- Diabetes $x Etiology
- Blood lipids $x Analysis
- Biochemical markers