National Institute of Diabetes and Digestive and Kidney Diseases 5U01DK135017-04

Integrative analysis of multi-omic signatures and cellular function in human pancreas across developmental timeline at single-cell spatial resolution

This award supports research on human pancreas development focusing on β cell mass establishment and maturation during pediatric stages, using single-cell multi-omic spatial data and living slice technology to understand type 1 diabetes pathogenesis and develop new therapies.

Description

Studies of human pancreas development have begun to elucidate influences in the establishment of β cell mass and formation of islets, but genetic and environmental influences that manifest during postnatal pancreas development remain unknown. The first decade of life (termed the pediatric period for this proposal) is a dynamic time in pancreas development when two critical processes occur: (1) β cell mass is established and (2) β cells and islets functionally mature. In addition, it is the time β cell-directed autoimmunity of type 1 diabetes (T1D) often begins. Thus, understanding the molecular and cellular processes that govern pediatric pancreas development and function is key to improving diagnosis and developing strategies to prevent or treat β cell dysfunction. Our proposal is based on exciting single-cell multi-omic spatially-resolved pilot data that will allow us to map the context specificity of T1D and related trait GWAS signals in pancreas across cell type, age, sex, and developmental stage. Using living slice technology, we will investigate cellular physiology and cell-cell communication in situ with high temporal resolution to provide insights into processes that govern β cell maturation and establishment of healthy pancreatic architecture. The overlay of spatial, physiological, transcriptional, and chromatin data from the same organs will provide unprecedented access to define changes in molecular signatures, tissue architecture, and β cell maturation. This research will provide new mechanistic insights about the functional maturation of human β cells during critical pediatric life stages, potentially influencing T1D pathogenesis understanding and leading to new therapies for diabetes and other pancreas diseases.

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