Author ORCID Identifier

0000-0002-5339-4619

Defense Date

2021

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmaceutical Sciences

First Advisor

Dayanjan S Wijesinghe

Second Advisor

Donald Brophy

Third Advisor

Erin Hickey Zacholski

Abstract

Abstract

Sickle cell disease (SCD) is a group of genetic disorder that occurs due to genetic mutation of a beta-globin gene that lead to production of pathogenic hemoglobin S (HB S). Genotypes of SCD include Hb SS (sickle cell anemia) which is the most common and severe form of SCD affects about 20 to 25 million people worldwide, HbSC, Hb Sβ+- thalassemia, and Hb Sβ0-thalassemia. SCD is characterized by multiorgan complications that, in turn, affect lipids composition. During hypoxia a sequence of changes will take place such as HbS polymerization, erythrocyte rigidity and stickiness, and oxidative stress. The combination of these changes will affect lipids components such as polyunsaturated fatty acids (PUFA), which are substrates for a significant number of bioactive lipids such as the eicosanoids and some of the endocannabinoids. For example, vaso-occlusion crisis, the most common cause of SDC hospitalization, is found to be accompanied by changes in PUFA components of RBCs cell membrane encompassing Omega-3 and Omega-6. This comprehensive review outlines lipid changes that accompany SCD and also identify the gaps in our knowledge. This review will also allow us to devise better treatment options to manage the different pathophysiology and complications of SCD.

Abstract:

Introduction: A common risk factor for infertility is obesity. The global rise of obesity accompanied with infertility has led to widespread adoption of assisted reproductive technologies such as in vitro fertilization (IVF) to achieve pregnancy. However, pregnancy outcomes such as embryo quality vary after IVF, possibly due to disruptions in metabolism. Previous metabolomic studies investigating embryo quality were limited to characterizing broadly lipid classes, or a few molecular lipid species. Here, we sought to determine specific circulating lipids and metabolites with matrix-specific effects that could serve as putative biomarkers of embryo quality, correlated with BMI, and predicted clinical pregnancy subsequent IVF.

Methods: Electronic health record (EHR) data, as well as lipids and metabolites obtained from follicular fluid (FF) and platelet poor plasma (PPP), were collected from women (n = 26) undergoing IVF. Lipids and metabolites were acquired via untargeted mass spectrometry. For embryo quality and BMI, we performed multiple linear regression analysis to find correlates. For 6 weeks pregnancy, we applied a linear discriminant analysis to select lipids and metabolites that allowed for group determination.

Results: Several lipids and metabolites were selected from both matrices (FF and PPP) that either outperformed models containing only EHR or added value to EHR models. In predicting embryo quality, glycerophospholipids obtained from PPP produced the best fit model. The predicted values include (LPC) 22:6 , phosphatidylcholine (PC) 16:1/22:6, and phosphatidylethanolamine-plasmalogen (PE-P) 16:0/22:6 were negatively correlated with 2PN while Phosphatidylethanolamine (PE) 18:0/20:3, lysophosphatidylethanolamine (LPE) 18:1, PC 14:0/16:1, and PE-P 16:0/20:5 were positively correlated with 2PN (R adjusted = 0.730, RMSE = 0.329). For rLDA of 6-weeks of pregnancy, the best model was the metabolite model obtained from Platelet Poor Plasma (misclassification = 3.85%, Entropy R-squared = 0.809).

The BMI multicomponent domain model obtained from FF, LPC 18:1, PC 16:1/22:6, and malic acid were negatively associated with BMI while Fasting insulin and PC 16:0/22:4 were positively correlated with BMI values (R-square adjusted = 0.819, RMSE = 0.127). However, the combined data model for FF has the best prediction of BMI values. In this model, PE-P 16:0/22:6, aspartic acid, and fasting insulin as positively correlated variables with BMI values, whereas indole-3-propionic acid was negatively correlated with BMI (R-squared adjusted = 0.856, RMSE = 0.113).

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-15-2021

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