Research Summary

Diabetes is a major biomedical problem afflicting 387 million worldwide, and causing one death every 7 seconds (IDF 2014). Intriguingly, 77% of world’s diabetics live in low- and middle-income countries, which have a low prevalence of obesity—the diabetes rates do not correlate with obesity rates. Further, a synergistic relationship exists between tuberculosis and diabetes in these countries leading to convergence of two major epidemics.

Current treatments for type 1 and 2 diabetes are symptomatic. The dysfunction and/or death of insulin-producing beta cells are a hallmark of type 1 and 2 diabetes. Therefore, identification of mechanisms for beta cell regeneration and prevention of beta cell dysfunction and death may afford an etiological treatment of diabetes.

Our goal is to identify molecules that regenerate beta cell mass and prevent beta-cell dysfunction and death. We also develop broadly-applicable chemical technologies with the intent of applying these technologies to specific avenues in beta cell biology. Below is a sampling of current research projects:

1) Exceptional organisms: Nature has evolved organisms that feed frequently  (e.g., humans) and those that feed infrequently (e.g., lions). While frequent feeding organisms are often studied (e.g., mice), it is the infrequent feeding organisms that survive conditions considered pathological to humans. We are unraveling the molecular mechanisms by which infrequent feeding reptiles avert metabolic disorders despite possessing lifestyles that will be pathological to humans. We draw inspiration from the studies on the infrequent feeding Gila monster that led to the diabetes drug exenatide.

 

2) Chemical Technologies: Motivated by key challenges in diabetes research, we are developing the following tools/methods:

 a) Protein Stability in vivo: Protein misfolding and aggregation are the key drivers of beta cell failure in type 2 diabetes. We are developing a general, sensitive, and label-free method that will accurately and precisely report on the changes in protein’s conformational stability and microenvironment in cellulo and in vivo.

 b) Beta cell imaging and therapeutic delivery: We are developing methods for targeted delivery of therapeutic and imaging agents to the beta cells in vivo.

 c) Next-generation genome-engineering: CRISPR-based technologies hold immense promise for therapeutic genome editing and transcriptional regulation in beta cells but suffer from several issues, including those about specificity and in vivo delivery. We are applying chemistry-based approaches to solve these issues.