Linking Islet Cell Function and Identity from in vitro to in situ

Contact PI: Patrick MacDonald, PhD, University of Alberta (U01 DK120447)

Emma Lundberg, PhD, Investigator, KTH Royal Institute of Technology
Seung Kim, PhD, co-Investigator, Stanford University
Rafael Arrojo e Drigo, PhD, Investigator, Vanderbilt University (09/01/2020-present)
Martin Hetzer, PhD, Investigator, Salk Institute (09/15/2018-09/01/2020)
Stephen Quake, PhD, Investigator, Stanford University (09/15/2018-09/01/2019)
Marjan Slak Rupnik, PhD, Collaborator, Medical University of Vienna
Andraz Stozer, MD, PhD, Collaborator, University of Maribor
Patrik Rorsman, PhD, Collaborator, University of Oxford
Linford Briant, PhD, Collaborator, University of Oxford

Start Date: September 15, 2018
End Date: August 31, 2022

Abstract

In type 1 diabetes (T1D) insulin producing b-cells of the pancreatic islets of Langerhans are lost and secretion of the glucose-raising hormone glucagon from a-cells is dysregulated, contributing to hyperglycemia and impaired counter-regulation. Recent studies show heterogeneity within the b-cell and a-cell populations both in vitro and in situ. For example, b-cell sub-groups differ in their Ca²⁺ signaling and gene expression profiles, and maybe even in their ability to survive in T1D. Understanding the variability and plasticity of human islet cell function, and the relationship of this to components of the islet microenvironment such as vasculature or nerves, is important since this may provide avenues for the discovery of new treatments such as the protection or regeneration of b-cells. Our proposal will combine in-depth gene and protein expression profiling and functional assessment on a cell-by-cell basis to understand the underlying regulation of islet cell heterogeneity and will map these in relation to other islet cells types and components of the local environment. Integration of an in-house human islet isolation program, multi-dimensional cell imaging expertise, and single-cell dual functional and gene expression profiling will help accomplish the goal of obtaining a high-resolution understanding of islet cells within their local tissue architecture in health and diabetes.