Functional characterization of T2D-associated genes and pathways

The ultimate objective of the Diabetes Research Group is to use human genetics to reveal novel biological mechanisms that inform understanding of T2D and ultimately its diagnosis, prevention, and treatment. As human genetic studies succeed in identifying genomic regions influencing diabetes risk, increasing effort is needed to translate these into a meaningful biological understanding of disease that can be used to improve public health.

More than 80 percent of T2D-associated variants lie in non-coding regions of the genome whose functional annotation is still difficult to interpret due to the cell type-specific and condition-specific nature of their activity. Dissecting the genetic basis of T2D therefore requires a concerted systematic effort to interpret both coding and non-coding variation and understand how it contributes to phenotypic variation in the context of the complete cellular machinery.

Teams of researchers within the Diabetes Research Group are developing and employing diverse biochemical, molecular, and cellular methods and animal models to determine the mechanisms by which genetic factors contribute to disease. The goals of these efforts are to:

  • Pinpoint causal genes and variants and the ways in which genetic variation disrupts gene and protein function
  • Identify the cellular and physiological pathways and processes that underlie the biological basis of disease, as these could represent important therapeutic targets for those with or at risk for developing T2D

As a complement to efforts centered on functionally characterizing specific genetic risk factors for T2D, the team also aims to determine genetic influences on disease-relevant cellular processes and pharmacological stimuli. Toward this end, Diabetes Research Group scientists are developing cell models and assays that read out cellular processes with well-established roles in disease, such as insulin secretion from the pancreatic beta cell and adipocyte differentiation and function. They are also developing and applying high-throughput, multi-modular methods in genome and variant editing for systematic assessment of molecular and cellular phenotypes coherent with T2D and the effects of genetic variation on cellular function and response.