Diabetes is a chronic disease characterized by the destruction or dysfunction of the insulin-producing pancreatic beta cells. My lab studies the mechanisms that regulate pancreas development with the idea that this will shed light on the key steps necessary to regenerate the beta cells lost in individuals with diabetes. In short, my lab uses animal models (mouse and zebrafish) and human donor tissue to understand what instructs cell growth and how these processes go wrong in disease.

Significant research in the field has focused on transcription as the mechanism driving pancreatic and beta cell development. Our discovery that polyamine and hypusine biosynthesis instructs pancreatic cell development expanded this view, as this finding showed that mRNA translation may also play a fundamental role in regulating cell growth. The polyamine and hypusine biosynthesis pathway has a distinct relationship with the process of mRNA translation. Specifically, eukaryotic initiation factor 5A (eIF5A) is the only known protein to contain the unique polyamine-derived amino acid hypusine (hydroxyputrescine lysine). The hypusinated form of eIF5A (eIF5A^Hyp) is generated through a multi-step reaction, which is initiated by the rate-limiting enzyme deoxyhypusine synthase (DHPS) and uses the polyamine spermidine as a cofactor to modify the lysine at position 50 of eIF5A. eIF5A^Hyp binds the ribosome and functions during mRNA translation to promote the elongation of a largely undefined subset of transcripts. Our work suggests that eIF5A^Hyp is required to instruct cell growth and differentiation in the pancreas. Ongoing studies in my lab are further interrogating this pathway to understand its role in pancreas development and diabetes pathogenesis.

In parallel with our analyses of hypusine biosynthesis in the pancreas, my lab is studying the impact of human DHPS mutations on clinical outcome. Our collaborative study, published in 2019, was the first description of DHPS Deficiency, a new human monogenic disease associated with impaired hypusine biosynthesis. Due to this discovery, my lab is investigating how human DHPS mutations drive altered growth and disease.