자료유형  

 학위논문

Control Number  

0016933594

International Standard Book Number  

9798379564322

Dewey Decimal Classification Number  

612

Main Entry-Personal Name  

McCann, Marc.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(127 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Advisor: Stringer, Kathleen A.;Zhu, Haojie.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Restrictions on Access Note  

This item must not be added to any third party search indexes.

Summary, Etc.  

요약Sepsis is a collection of clinical signs and symptoms that is described by life-threatening organ dysfunction inflicted by the body's own response to infection. The pathophysiological origins of organ dysfunction are not well understood, but mitochondrial metabolic dysfunction has been implicated as an influential factor. Serum lactate levels, a metabolite biomarker, are currently used to evaluate metabolism in patients with sepsis. Although lactate is clinically useful in many patients, overreliance on this single metabolite obfuscates the many disturbed metabolic pathways that likely influence the progression of sepsis-induced organ dysfunction. The carnitine pool represents a family of metabolites that are well-established markers of disturbed mitochondrial fatty acid oxidation. Recently, our group and others have identified elevations in acetyl-L-carnitine (C2) as the acylcarnitine with the most robust associations with sepsis-induced organ dysfunction, mortality, infection, and inflammation. The focus of the dissertation was to establish connections between C2 and various markers of mitochondrial dysfunction to mechanistically credential C2 as a candidate biomarker by expanding the metabolic interpretation of the signal in sepsis. Developing multiple linear regression models with stepwise forward-backward variable selection, I identified metabolite signatures that were significantly associated with platelet derived mitochondrial oxygen consumption rates. One of the models included a negative association between whole blood C2 concentrations and baseline mitochondrial oxygen consumption rate, indicating that elevated C2 in the blood could represent lower mitochondrial function. Leveraging serum baseline concentration data from patients with septic shock, I identified a relationship between mortality and measurements of C2 and individual intermediates of the tricarboxylic acid (TCA) cycle, a key step in energy production via oxidative phosphorylation. I used multiple linear regression models to determine that septic shock non-survivors at 28-days and 1-year had a stronger relationship between C2 and malate, when compared to survivors. I also employed a mouse model of sepsis in conjunction with data from human sepsis and septic shock cohorts to characterize the tandem progression of sepsis-induced organ dysfunction and metabolic disturbances that present throughout sepsis. In the sepsis mouse model, I observed whole blood measurements of L-carnitine (LC) and the C2/LC ratio were decreased and increased, respectively, in the septic animals compared to the controls. This finding suggests that measuring carnitine metabolism has diagnostic value as an early predictor of sepsis. Analysis of the human cohorts revealed perturbations in the carnitine pool (LC, C2, C2/LC) were present and positively associated with various assessments of organ dysfunction. I also discovered perturbed metabolic pathways in the kidneys and livers of the septic animals that precede widespread, clinically detectable organ dysfunction and damage. Many of these organ metabolite signatures were correlated to changes in the whole blood C2/LC ratio, suggesting the whole blood C2/LC ratio reflects a broad range of metabolic abnormalities at the organ level. Additionally, several of the sepsis-induced organ metabolic disturbances in the animals were detected and associated with organ dysfunction in the human cohorts, including histidine, malate, alanine, glutamate, aspartate, lactate, and glutamine. These findings provide a mechanistic link between the metabolic response with the onset and progression of sepsis-induced organ dysfunction. Overall, various markers of mitochondrial metabolic dysfunction were found to have profound connections to blood measurements of C2. This work provided evidence to support the use of C2 as a candidate biomarker for the comprehensive assessment of metabolism in patients with sepsis.

Subject Added Entry-Topical Term  

Pharmaceutical sciences.

Subject Added Entry-Topical Term  

Physiology.

Subject Added Entry-Topical Term  

Biomedical engineering.

Index Term-Uncontrolled  

Metabolomics

Index Term-Uncontrolled  

Sepsis biomarker

Index Term-Uncontrolled  

Precision medicine

Index Term-Uncontrolled  

Mitochondrial function

Added Entry-Corporate Name  

University of Michigan Clinical Pharmacy Translational Science

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:640599