Date of Award

Spring 1-1-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy Degree

Department

Chemical And Biomedical Engineering

First Advisor

Gatica, Jorge E.

Second Advisor

JOANNE M. BELOVICH

Third Advisor

NOLAN B. HOLLAND

Abstract

Regulation of brain metabolism and cerebral blood flow involves complex control systems with several interacting variables at both cellular and organ levels. Quantitative understanding of the spatially and temporally heterogeneous brain control mechanisms during internal and external stimuli requires the development and validation of a computational (mathematical) model of metabolic processes in brain tissue. A computational model of the biochemical pathways in brain is presented in this paper. The model structure consists of neurons, astrocytes, and a surrounding capillary network. Glucose is the major oxidative energy substrate in the brain. However, under hypoglycemic conditions such as during diet or fasting or other conditions induced by pathology, alternate energy substrates such as ketone bodies supplement glucose metabolism. In this study, the increased activity of the glutamate-glutamine shuttle is studied in conjunction with the observation that ketosis results in lower lactate levels in brain. A model of ketosis in brain is used to examine the partitioning of carbon units entering the tricarboxylic acid cycle at the level of acetyl-CoA. Using Flux Balance Analysis, we hypothesized that the carbon fluxes would shift towards an increase in flux rates stemming from the metabolism of ketone bodies with a proportional decrease in the flux of lactate derived from the astrocyte-neuron lactate shuttle. It was found that the model could predict an estimation of compartmentalized flux-balances (mitochondrial cytosolic) in standard and ketogenic diet conditions. Ketone body metabolism was found iii to be loosely coupled with glucose metabolism (astrocyte-neuron) suggesting important therapeutic implications

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