Utilizing Metabolomics and Proteomics for Clinical Applications

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Kadesha S McIntyre (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Medical conditions such as heart failure and infant outcomes related to in utero drug exposure have become prevalent amongst the world population. As we observe alarming trends in poor health choices, treating these conditions have become of grave concern. While medical professionals work to optimize treatment and prevention plans, a greater and more robust tool is needed to aid in this endeavor. Recently, there has been an emergence in proteomic and metabolomic based approaches to gain understanding into a diseased state of a biological. Though mainstream in the lab, these methods have yet to be applied in clinical settings. Utilizing these techniques, this study has two primary goals: 1) Explore effects of in utero drug exposure on nutrient metabolites in fetal tissue, and 2) Discover and map pathways of MMP-9 peptide targets within the heart tissue. While it is known that drugs disrupt the normal metabolic processes involved throughout infantile development, their exact biochemical mechanisms are unknown. Utilizing umbilical cords, Aim 1 of this study hypothesized that exposure to drugs during neonatal development would lead to perturbations of key nutrient metabolites levels known to assist in cognitive and physical development in fetal tissues. Targeted drugs of abuse screened for in this study included (1) cocaine with benzoylecgonine (BE) and ecgonine methyl ester (EME), (2) methadone with 2-ethylidene-1,5dimethyl-3,3-diphenylpyrrolidine (EDDP), (3) fentanyl with acetyl norfentanyl, (4) heroin with 6-monoacetylmorphine (6-MAM), (5) nicotine with cotinine, (6) buprenorphine with norbuprenorphine, (7) oxycodone with noroxycodone, and (8) (+)-11-Nor-Δ9-THC-9-carboxylic acid glucuronide (THC-COOH glucuronide). Of the 27 umbilical cords reported as exposed, 8 tested positive for methadone and EDDP, 9 for cotinine, 2 for norbuprenorphine, and 1 for acetyl norfentanyl. 7 remaining cords were reported as being exposed from corresponding participants. However, these substances were outside of this study"s panel of detection. Focusing on thiamine, proline, tryptophan, aminobenzoic acid, valine, and nicotinamide metabolite comparisons between controls and positive samples, we saw unusual trends in nutrient concentrations. Compared to controls, cords exposed to methadone had upregulated thiamine (p-value: 0.004), proline (p-value: 0.024), and aminobenzoic acid (p-value: 0.027) concentrations. Like the methadone exposed specimen, cotinine positive samples had upregulations in thiamine (p-value: 0.037), proline (p-value: 0.001), and aminobenzoic acid (p-value: 0.012) when compared to controls. In addition, there were upregulations in valine (p-value: 0.017), tryptophan (p-value: 0.023), and nicotinamide (p-value: 0.033) concentrations as well. These overall trends suggest that methadone and nicotine (cotinine) exposure can cause certain nutrient upregulations in fetal tissue.Elevated levels of MMP-9 in the heart after myocardial infarction (MI) correlate with subsequent diagnosis of heart failure, due to its role in driving inflammation. As a method to suppress MMP-9 activity in the LV and reduce progression to heart failure, previous studies have used MMP-9 inhibitors.6 However, these were not successful, in part, due to the lack of inhibitor specificity. Hoping to better understand the progression of heart failure and develop efficient MMP-9 targeted therapeutics, Aim 2 hypothesis was to utilize proteomics to derive a comprehensive list of MMP-9 LV substrates. Of the 89 discovered MMP-9 targets, three: myosin regulatory light chain 2, ventricular/cardiac muscle isoform (Myl2), F-actin-capping protein subunit alpha-2 (Capza2), and cofilin-1 (Cfl1) were linked to adverse cardiac function and remodeling.

Additional Information

Publication

Thesis

Language: English

Date: 2020

Keywords

LCMS, Metabolomics, Proteomics, Prenatal drug exposure and related infant nutrient outcomes, MMP-9 roles in heart failure

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