Project Grant R16GM154691

NUMERICAL EXPERIMENTATION OF THE THERAPEUTIC EFFECT OF EXCESS GLUCOSE TRANSGLYCOSYLATION AND OPTIMIZATION IN THE PROXIMAL SMALL INTESTINE. - PROJECT SUMMARY/ABSTRACT THE GASTROINTESTINAL (GI) SYSTEM ENGAGES THE COORDINATED FUNCTION OF DIGESTIVE ORGANS, OXYGENATED BLOOD SUPPLY, NUTRIENT PROCESSING AND DISTRIBUTION, DETOXIFICATION OF NOXIOUS SPECIES, AND SEQUESTRATION OF EXCESS BIOACTIVE NUTRIENTS TO MAINTAIN HOMEOSTASIS AND RESPOND TO THE BODY'S NUTRIENT BIOAVAILABILITY. EXCESS GASTROINTESTINAL-PRODUCED BIOACTIVE NUTRIENTS SUCH AS GLUCOSE OR FRUCTOSE, PRECURSORS TO MANY GASTROINTESTINAL-RELATED DISEASES, POSE A MAJOR BURDEN AND RISK TO THE LIVER DUE TO INCREASED HEPATIC METABOLISM PHYSIOLOGICALLY DESIGNED TO PROCESS AND SEQUESTER EXCESS BIOACTIVE NUTRIENTS WITHIN DESIGNATED TISSUES OF THE BODY. EXCESS GLUCOSE AND FRUCTOSE DUE TO DYSREGULATION AND HIGH SUGAR CONTENT DIETS ARE AMONG THE MANY CONTRIBUTORS TO NON-ALCOHOLIC FATTY ACID (NAFLD) PATHOGENESIS WITH FRUCTOSE HAVING MORE POTENTIAL IMPACT ON THE ETIOLOGY OF THIS DISEASE THAN GLUCOSE SINCE IT IS ONLY METABOLIZED IN THE LIVER. IN ADDITION, FRUCTOSE METABOLISM TO FATTY ACID IN THE LIVER IS FAR LESS REGULATED THAN ITS GLUCOSE COUNTERPART. HOWEVER, GLUCOSE BEING AN ISOMER OF FRUCTOSE, WILL BE USED AS THE MODEL COMPOUND FOR THE PROPOSED APPROACH OF REMEDIATING AND OPTIMIZING EXCESSES OF THESE TWO HEXOSE MOLECULES (GLUCOSE AND FRUCTOSE) IN THE PROXIMAL SMALL INTESTINE. THE OBJECTIVE OF THIS RESEARCH PROJECT IS TO DETERMINE THE OPTIMAL DYNAMICS FOR EXCESS GLUCOSE REMEDIATION VIA FIBRATION IN THE PROXIMAL SMALL INTESTINE (SI) LUMEN. THIS WILL BE ACCOMPLISHED BY IDENTIFYING AND QUANTIFYING MECHANISMS OF SPECIES TRANSPORT AND PHYSICOCHEMICAL TRANSFORMATION AT THE PROXIMAL SMALL INTESTINE WITH A FOCUS ON GLUCOSE BIOAVAILABILITY OPTIMIZATION AND EXCESS REGULATION. DETERMINE THE OPTIMAL RATES OF GLUCOSE FIBRATION RELATIVE TO OTHER TRANSPORT AND METABOLIC REACTION RATES AT THE PROXIMAL SMALL INTESTINE. GI SYSTEMS USE BIOPHYSICAL AND BIOCHEMICAL MECHANISMS IN COORDINATING SPECIES TRANSPORT AND TRANSFORMATION COUPLED WITH INTERACTIONS WITH THE WALL OF THE GI LUMEN. A SYSTEMATIC REPRESENTATION OF THESE MECHANISMS WILL SERVE AS A PLATFORM FOR THE DEVELOPMENT OF A NUMERICAL MODEL THAT CAN ASSIST IN GLUCOSE TRANSPORT AND TRANSFORMATION RATE QUANTIFICATION IN THE PROXIMAL SI. WHILE ALSO ASSESSING THE OPTIMAL RATE OF GLUCOSE CONDENSATION TO DIETARY FIBER (NDO) INVOLVING THE TRANSGLYCOSYLASE ENZYME IN THE PROXIMAL SI. THE PROCESSES GUIDING THE OPTIMAL RATE DETERMINATION ENCOMPASS BOTH THE SPECIES TRANSPORT IN AND OUT OF THE PROXIMAL SI AND THE SERIES OF SPECIES TRANSFORMATIONS IN THE SAME. A COMPARTMENTAL METABOLIC RATE MODEL FOR THE PROXIMAL SI AND OTHER SUPPORTING ORGANS SERVING AS PERIPHERAL COMPARTMENTS WILL BE DEVELOPED TO MODEL GLUCOSE FORMATION, CONSUMPTION THROUGH TRANSGLYCOSYLATION, ABSORPTION, AND REGULATION RATES WITH THE FOCUS OF OPTIMIZING ITS BIOAVAILABILITY AND REGULATING ITS EXCESS THROUGH TRANSGLYCOSYLATION (NDO FORMATION). THE NUMERICAL MODEL FOR THE QUANTIFICATION AND ANALYSIS OF THE PROPOSED METABOLISM MECHANISMS WILL BE DEVELOPED AND SOLVED IN MATLAB (AND COMSOL MULTIPHYSICS AS AN ALTERNATIVE). THIS EFFORT WILL CREATE A SYSTEMATIC GASTROINTESTINAL TRACT VIRTUAL LABORATORY PLATFORM WHERE DETAILED SPECIES TRANSPORT AND TRANSFORMATION MECHANISMS CAN BE READILY ASSESSED AND QUANTIFIED. THIS MODELING APPROACH CAN LEVERAGE OUR UNDERSTANDING OF MANY GASTROINTESTINAL PATHOPHYSIOLOGICAL CONDITIONS CONNECTED TO EXCESS GLUCOSE IN THE BODY AND PROVIDE A SYSTEMATIC APPROACH TO DEVELOPING DIAGNOSTIC PROCEDURES AND THERAPEUTIC PRESCRIPTIONS PER DISEASE OF INTEREST.