First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell...

Area of Science:

• * Developmental Biology
• * Pharmacology
• * Zebrafish Models

Background:

• * Whole-organism chemical screening accelerates drug discovery.
• * In vivo screening throughput lags behind in vitro assays.
• * Novel methods are needed to enhance in vivo screening capacity.

Purpose of the Study:

• * To develop an automated in vivo high-throughput screening (HTS) platform for drug discovery.
• * To identify FDA-approved drugs that increase pancreatic beta cell mass using zebrafish.
• * To explore signaling pathways regulating beta cell regeneration.

Main Methods:

• * Developed automated reporter quantification in vivo (ARQiv) combined with robotics for HTS (ARQiv-HTS).
• * Screened over 500,000 transgenic zebrafish larvae using cell-specific fluorescent reporters.
• * Quantified drug-induced changes in insulin-producing beta cells.

Main Results:

• * Identified 24 FDA-approved drugs that induce endocrine differentiation and/or stimulate beta cell proliferation.
• * Discovered novel roles for NF-κB signaling in endocrine differentiation.
• * Identified serotonergic signaling as a stimulator of beta cell proliferation.

Conclusions:

• * ARQiv-HTS is a powerful platform for whole-organism drug discovery.
• * Identified key signaling pathways regulating beta cell mass.
• * Findings offer potential therapeutic targets for diabetes treatment.