Short bowel syndrome (SBS) is a condition in which nutrients are not properly absorbed because a large part of the small intestine is missing or has been surgically removed. To meet caloric needs, SBS patients frequently require an expensive treatment called long-term parenteral nutrition. But this therapy results in high complication rates, and mortality rates also remain high. During late embryogenesis, intestinal lengthening far outpaces body growth, becoming exponential in both humans and rodents. Postnatally, intestinal lengthening slows and resumes a linear relationship between intestinal length and body weight. Fibroblast growth factor 9 (FGF9) and Wnt/ß-catenin have been identified as the primary regulators of exponential intestinal longitudinal growth. Thus, the goals are to understand how these factors accelerate intestinal growth, to exploit a well-defined mouse surgical model of SBS, and to use this knowledge to develop novel therapeutic approaches.
• Identify the molecular mechanisms by which mesenchymal FGF and Wnt/ß-catenin signaling regulates longitudinal growth of the small intestine
• Test the hypothesis that up-regulation of FGF9 and Wnt/ß-catenin signaling in the intestinal mesenchyme in vivo can enhance longitudinal growth and adaptation in a murine surgical model of SBS
Potential impact: The overall goal is to develop novel therapeutic approaches for the clinical management of SBS in children within the next decade.