Research

Mission:

Gain fundamental insight into basic and biomedical science through the rigorous investigation of the genetic mechanisms regulating organogenesis and disease.

Current Focus:

1. Determine how progenitor and stem cells are programmed to differentiate and renew themselves in the context of vertebrate liver and pancreas development, homeostasis, and regeneration, and of human stem cell differentiation. We aim to decipher progenitor biology to the depth that will allow us to genetically and pharmacologically manipulate differentiation in vivo.

2. Establish mechanistic insight into genetic diseases associated with liver or pancreas dysfunction by developing and analyzing more reliable animal disease models that will also be adaptable for in vivo drug testing/discovery.

Approaches:

1. Using a genetically amendable vertebrate model system, the zebrafish, we are currently investigating how transcription and signaling factors regulate progenitors of the pancreas and liver. With insight from these studies and new genetic technologies that we have developed, we are identifying the combination of genes and/or small molecules that can induce new liver and pancreatic tissues through in vivo genetic reprogramming.

2. Generate and analyze human iPSC and zebrafish models of heritable diabetes and use these models to investigate disease mechanisms and test potential drugs.

3. Develop new genetic technologies to more precisely and efficiently manipulate gene function for use in research and therapeutics.

Lab Interests:

in vivo reprogramming, monogenic/polygenic diabetes, MODY5, GWAS, RCAD, biliary atresia, signal transduction, epigenetics, diseases of the pancreas and liver, in vivo chemical biology/screens, regeneration, animal disease models, precision medicine, pattern formation, lineage specification, regeneration, evolution of endoderm organs …

Why Zebrafish? – The zebrafish is an in vivo model that allows scientists to rapidly, rigorously, and efficiently investigate the impact that genes and chemicals have on vertebrate biology.

Personalized Medicine

As more people gain access to their individual genetic data, more questions arise regarding anomalies uncovered from the analysis of their genomic sequence. While certain anomalies can be accessed based on published research or by a predictive bioinformatics approach, others will require more definitive functional studies to better understand the potential affects of the mutation on gene function and on the health of the individual. Our lab’s expertise in liver and pancreas biology allows us to investigate genetic anomalies associated with diseases related with these organs. With our animal model and technologies that we are developing in the lab, we can examine the expression and function of the gene effected and model the effect of the mutation in a vertebrate system. Our goal is to rapidly access the functional consequences of the human mutations identified.

Diabetes - A Precision Approach

The broad classification of disease subtypes often masks their mechanistic heterogeneity as well as their potential similarities. For example, diabetes studies typically emphasize either early or late onset diabetes or polygenic or monogenic diabetes, i.e., Type 2 Diabetes (T2D) versus Maturity Onset Diabetes of the Young (MODY). Based on the genes implicated in T2D by genome wide association studies (GWAS) and in monogenic diabetes, a variety of different genetic mechanisms may be contributing to this disease, supporting the idea that T2D is comprised of multiple etiological classes. By recognizing and understanding a patient’s disease subtypes based on genetic mechanism, we will be better able to design targeted and precise drug screens and therapeutics.

We are currently focusing on HNF1B associated diabetes. HNF1B is one of few genes implicated in both T2D and monogenic diabetes (MODY5). Our lab has developed the only existing vertebrate genetic animal model that reliably mimics the liver insulin resistance and pancreas defects associated with HNF1B diabetes (MODY5, RCAD). We are currently utilizing this zebrafish mutant diabetes model to test whether candidate compounds, including those identified from previous studies, will have potential therapeutic value for HNF1B diabetes. To identify new lead compounds, we will screen for small molecules that can rescue insulin/glucose response and/or ß-cell number in whole hnf1b mutant juvenile zebrafish. We reason that because partial loss of Hnf1b function is characteristic of both MODY5 patients and our zebrafish Hnf1b diabetes model, compounds screened may need only to attenuate the effect of Hnf1b partial loss of function to mitigate HNF1B pathologies. Due to the lack of a suitable Hnf1b partial loss of function mouse model of MODY5, we plan to generate human pluripotent stem cell (hPSC) models of MODY5 HNF1B haploinsufficiency – to utilize as a platform to further validate these compounds. We therefore are in the process of identifying individuals and families carrying HNF1B mutations who are willing to donate their cells for our studies.