SNIC
SUPR
SNIC SUPR
singlecellnew
Dnr:

SNIC 2018/8-26

Type:

SNAC Small

Principal Investigator:

Jeremie Charbord

Affiliation:

Karolinska Institutet

Start Date:

2018-01-17

End Date:

2019-02-01

Primary Classification:

10610: Bioinformatics and Systems Biology (methods development to be 10203)

Webpage:

Allocation

Abstract

Diabetes, a devastating disease affecting nearly 350 million persons worldwide, is characterized by depletion of the pancreatic endocrine β-cells. At the cellular level two major strategies to increase the ß-cell pool consist in 1) increasing ß-cell proliferation and 2) transdifferentiating other pancreatic cells to ß-cells. Using zebrafish we have developed high-throughput screening methods to identify potent small-molecules promoting these processes and confirmed the effect of selected drugs on ß-cells from mouse pancreatic islets. Our present aim is to determine the gene regulatory networks implicated in the processes following drug administration, which is necessary to fully understand the mechanism of action of the drugs, identify their final molecular target(s) and the pathways leading to the target(s) activation, outline potential side effects, and select new molecular hubs that may serve for further drug discovery. To address this question, we have performed single-cell RNA-seq of drug- and negative control-treated samples at different time points. Differentially expressed genes were then identified and, by means of gene correlation analyses, gene networks were established. These gene networks characterize the different cell states at the different time points. To identify the regulatory factors (e.g. transcription factors) driving the expression of the genes belonging to the networks, further bio-informatics analyses are required, which is the purpose of the present request. The resulting regulatory hubs will be validated by gain and loss of function studies in different models (zebrafish, mice and, if possible, humans). This work might not only provide novel therapeutics to treat diabetes, but also give mechanistic insights into the multiple cellular states in ß-cell proliferation and transdifferentiation.