MAPLE SYRUP URINE DISEASE BLOCKED PATHWAY OF BCAA CATABOLISM

 Its being proposed that therapy with phenyl butyrate in MSUD patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake. Hypothesis

RATS (Rattus norvegicus) Age (10-30 days old) The physiology is easier to monitor in the rat The physiology is more like the corresponding human condition The distance effects of drug administration to specific anatomical areas Over time, a volume of data has developed that will take years to be replicated in the mouse. RESEARCH SUBJECTS

BCAA Catabolism

BCKDH

Specific Aim: To increase the proportion of active BCKDH. In order to see how phenyl butyrate increases the activity of BCKDH enzyme, the following procedure will be followed;  In vitro testing with fibroblast cells from rat  In vivo testing with rats  In vivo testing with human subjects RESEARCH DESIGN

In vitro Test (Fibroblast)  Four Rats : 2 healthy control, 2 MSUD patients  2 induced with MSUD via BCAA IV administration  Fibroblast cells are collected from subjects  2mm phenyl butyrate  CIC

 Based on the success of the in vitro test, a similar test is carried out in humans and the serum levels of BCAA and BCKA data before and after administration of phenyl butyrate generates charts for comparison. In vivo testing with Human Subjects

Results In vivo with Human Subjects

PROPOSED MECHANISM

Team A rats are orally given a saline solution for three days Team B rats are orally given phenyl butyrate for three days. After 3 days they are sacrificed, livers harvested and analysed using western blot In vivo with Rats  Results

 It contains Na+ hence, patients on salt diet cannot use  It can cause drowsiness  It contains inactive ingredients that may cause allergic reactions Side Effects of Phenyl butyrate

 INNOVATION:  Lactating Porcine Mammary Tissue Catabolizes Branched-Chain Amino Acids for Glutamine and Aspartate Synthesis Future Directions

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