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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Dissecting the role of islet non-ß populations’ identity maintenance in the development of monogenic diabetes

Alternative title: Forstå kva rolla oppretthalding av ikkje-ß øycelle populasjonsidentitet har knytt til utvikling av monogen diabetes

Awarded: NOK 10.4 mill.

By studying the monogenic versions of diabetes, we discovered that besides ß-cells, other endocrine cell types located in pancreatic islets present progressive cell fate errors (such as mixed hormone production), which characterize the overt diabetes contexts in mice. By using both human and mouse disease models of the most common monogenic diabetes disorder we started (1) characterizing these cells, (2) establishing the causality relationship with diabetes, (3) verifying if they are also present in humans. We now established good cellular and molecular tools for identifying the mixed identity cells as well as efficient genetic murine models for ablating (removing) them. Briefly, we set up a single cell transcriptomics pipeline with reliable results in the context of CRISPR-based human disease models as well as very efficient murine transgenic systems capable to specifically ablate (destroy), in vivo, the cells of interest according to their hormonal identity. We are now working at characterizing the cell fate profiles and causality relationship by using variation in the glycemia profile, islet architecture and molecular fingerprints as readouts. Moreover, we were now able to confirm an increase presence of these mixed identity cells in human islets from type 1 and type 2 diabetic donors, confirming it as an evolutionary conserved pathological event. As a by-product of this research, we also uncovered a relationship between the studied monogenic disease gene, immune system and chronological ageing as well as stemmed a soon to be published study revealing a previously unknown relationship during early insulin producing ß-cell differentiation between the same gene and a well-known developmental signalling pathway.

Diabetes mellitus represents a group of energy metabolism diseases defined by chronically increased blood sugar levels (hyperglycemia) triggered by the inability of the body to produce and/or use sufficient insulin. Insulin is a hormone synthetized by the ß-cells, which reside in the pancreatic islets alongside several other mono-hormonal endocrine cell types (islet non-ß-cells). The contribution of these neighboring cells identity maintenance errors or altered proportions to diabetes development is unknown. Here we plan to bridge this knowledge gap by using mouse and human models of monogenic diabetes. In vivo analysis of the recently developed murine model identified errors in islet non-ß-cells identity maintenance, characteristics for the contexts of overt diabetes. By using a wide range of transgenic and profiling tools we now aim to (1) characterize the origin and molecular fingerprint of these cells, (2) establish the causality relationship with diabetes, (3) verify if they are present in equivalent induced stem cells-based human disease models and finally (4) examine their read-out in a monogenic diabetes patient cohort. Uncovering the causality between the occurrence of islet non-ß-cells with mixed identity and diabetes onset and progression will offer new insights into the mechanism involved in islet homeostasis maintenance. Furthermore, if proven to be conserved in humans, this research will open potential new treatment avenues.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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