Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Sandy Westerheide, Ph.D.

Committee Member

Charles E. Chalfant, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Committee Member

Narasaiah Kolliputi, Ph.D.

Keywords

5-HETE, 5-oxo-ETE, C1P, ceramide kinase, Lipidomics

Abstract

Inflammatory wounds, both chronic and acute, lead to increased morbidity and mortality rates, especially in the elderly population. The annual healthcare cost for chronic wound care alone is over $39B in the US and the demographic of susceptible patients is steadily increasing due to an aging population and lifestyle-related diseases (e.g., hyperlipidemia, obesity, and type 2 diabetes). In fact, many chronic wounds currently have a worse 5-year outlook than certain types of cancers. This shows the need for expediting the wound healing process in such a way that compresses inflammatory signaling and encourages wound resolution without sacrificing pathogen removal and tissue integrity. A patient’s “lipid fingerprint” of sphingolipids and eicosanoids has recently emerged as a unique field of study, dubbed “lipidomics”, to better explain the complex molecular milieu of the mammalian inflammatory response in many common diseases such as wound healing and sepsis. Based on a decade of prior research from our lab and others, we hypothesize that specific changes in sphingolipid and eicosanoid profiles can enhance the proficiency of wound healing and quell the severity of inflammatory response. We propose the mechanism of C1P production by the enzyme CERK and subsequent interaction with cPLA2α as principal therapeutic targets for shifting eicosanoid production toward wound resolution (e.g., elevated HETEs). The research contained in this dissertation builds upon previous work from our lab but expands the purview of acute wound healing to the onset of inflammation and offers unique insight into neutrophil migration velocity and cellular behaviors (e.g., “N1” vs “N2”). Furthermore, we demonstrate that 5-oxo-ETE signals through a murine OXER1 receptor to modulate PPP activity, and that in vivo post-injury C1P inhibition is a viable approach to accelerating the wound healing process. Using a mixture of animal models and ex vivo cell culture assays combined with modern lipidomic techniques and traditional biological analyses we validate the physiological benefits of post-injury C1P inhibition and the anti-inflammatory effect of 5-oxo-ETE signaling through OXER1. These novel findings present promising therapeutic targets for future clinical studies regarding acute and chronic wound healing, sepsis, and other inflammatory diseases.

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