Request for Funding
Medical Student Research Fellowship for Summer 2011

All descriptions must contain enough detail to permit an assessment of the problem that is to be addressed and the methodologies that are to be employed. Please be careful to outline the role that the student will play in the project that is described. Please ensure that all relevant approval numbers (IRB, IACUC) are provided.

Mentor: James F. Amatruda and Ralph DeBerardinis                
Department:   Pediatrics     
Room number: ND3.120C  
Mail Code:     8534  
Phone number: 8-1645       
E-mail:            james.amatruda@utsouthwestern.edu      
Project title:               

Human subjects IRB approved project number (where applicable):      

Animal subjects IRB approved project number (where applicable):       2007-0228

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Animal-based
Brief Description of Project:
It has been shown that tumors demonstrate a unique metabolic phenotype with two key features. First, tumors display ‘aerobic glycolysis’, or preferential use of the glycolytic pathway for ATP production even in the presence of oxygen, a phenotype termed the Warburg Effect. Second, transformed cells become a “factory for macromolecular biosynthesis” to meet the metabolic and synthetic demands for rapid proliferation. Tumor cells shunt glycolytic intermediates down nucleotide biosynthesis pathways, remove intermediates of the TCA cycle for lipid biosynthesis, and use glutamate anaplerotically as a source for ATP production.

We hypothesize that this unique metabolic phenotype represents a reactivation of early developmental pathways and therefore mimics embryonic metabolism. Zebrafish embryos provide an ideal model, as they represent a “closed metabolic system”, meaning that in very early development all nutrients come from an internal source, the yolk. This allowed us to measure key components of the metabolic profile with little external background. Metabolite analysis of ZF embryos showed the presence of glucose and ammonia in the yolk at 2, 24, and 36 hours post fertilization. In addition, RT-PCR techniques were used to determine RNA expression of various metabolic enzymes before and after the mid-blastula transition (MBT) of the embryo. The MBT is an important time point in the development of the ZF embryo, as this is when the embryo begins to synthesize its own RNA and no longer relies on maternal transcripts. Distinct patterns of expression of important metabolic enzymes were seen pre and post MBT.

The purpose of this project is to follow up on these preliminary findings.  Specifically, we are interested in determining the functional significance of the change in metabolic enzyme expression that occurs at MBT.  This project will use metabolic profiling, developmental biology and gene knockdown techniques.

Previous Research Activities or Publications with Medical Students:
David Zhang:  Genetics of the DNA damage response
Matt Campbell:  Metabolic Profiling of Early Development