Rodolphe Dusaulcy

Hjelt grant holder 2020

University of Geneva

Diabetes is defined by chronic hyperglycemia which may lead to dangerous complications. Type 2 diabetes and type 1 diabetes are the best known forms. Type 2 is often associated with obesity, while type 1 is an autoimmune disease where the immune system destroys the insulin-producing pancreatic beta cells. The form of diabetes studied here is called “monogenic”, and is caused by a mutation in a single gene. These monogenic diabetes forms represent up to 4% of diabetes cases in pediatric populations and are characterized by alteration of beta cell function and or beta cell mass reduction.

Our objective is to identify and validate new genes and mutations responsible for monogenic diabetes. We previously sequenced over 400 genes potentially implicated in diabetes in a population of children with a suspicion of monogenic diabetes. We thereby identified a series of sequence variants in novel and known genes that constitute potential new monogenic diabetes genes and variants.

We hypothesize that these variants may reduce the capability of beta cells to adapt and resist to stressors such as fat and sugar excess or inflammatory mediators. We propose to study in vitro, in human and mouse beta cells, the specific impact of the identified genes and variants. On one hand, we will silence the expression of target genes and, on the other hand, reproduce in vitro the variants observed in diabetic children. To do that, we plan to use a new technology, called the Crispr/Cas9 system, to reproduce the sequence variants in beta cells. Then, we will study the consequences of these gene defects at molecular and functional level by assessing the impact on insulin production and release, cell proliferation and survival.

We believe that this project will be helpful for diabetic children and will allow a better understanding of disease development, adaptation and personalization of the treatments as well as the potential development of new therapeutic strategies.