# In vivo HTS assay for novel modulators of Apolipoprotein B

> **NIH NIH R01** · CARNEGIE INSTITUTION OF WASHINGTON, D.C. · 2020 · $645,300

## Abstract

Apolipoprotein-B (ApoB) is both a biomarker and a causal mediator of many central hallmarks of metabolic
disease, including insulin resistance, fatty liver disease, atherogenesis, endoplasmic reticulum stress, and
chronic inflammation. ApoB therefore serves as a useful phenotypic readout for the identification of
compounds that engender diverse metabolic benefits. The present proposal will perform a high-throughput
screen (HTS) to identify novel ApoB-lowering compounds using an automated robotics platform that enables
screening to take place in live larval zebrafish using a genetically encoded chemiluminescent reporter to
sensitively detect ApoB levels in individual fish. To accomplish this effort, we have brought together a team
of scientists all located at Johns Hopkins University and leaders in their respective fields. Farber has
established the zebrafish as a model for studies of vertebrate lipid metabolism, Mumm has created a powerful
HTS zebrafish screening platform, Ahima is a world leader in mammalian energy metabolism and Lectka is
an established chemist bringing significant expertise in screen hit prioritization to the effort. The HTS will take
place in two iterations, with the first iteration screening a ~3,000 compound library of clinically approved
compounds so that hits can be rapidly repurposed to treat a host of disease associated with Apob
perturbations. The second iteration screening is much larger effort to maximize compound diversity (30,000
compounds) and discover potentially entirely new avenues for treatment. Hits from the both screens will be
subjected to a high-content secondary screen that uses an automated imaging platform to monitor effects on
disease progression using a panel of transgenic zebrafish carrying fluorescent reporters of several important
metabolic disease risk factors. This secondary screen will efficiently classify and prioritize hits from the
primary screen and identify the subset of compounds with validated metabolic benefits in live vertebrate
organisms that justify further investigation and therapeutic development. Promising compounds from primary
and secondary screening will also be validated for activity in mammalian models, including mouse and human
cultured cells. The results of these efforts will be the first ever whole animal HTS for ApoB modifiers coupled
with a high-content secondary screen that together will enable the rapid identification of compounds to
ameliorate many metabolic disease phenotypes, as well as a collection of hits for the development of novel
therapies to combat the growing global burden of metabolic disease.

## Key facts

- **NIH application ID:** 9976330
- **Project number:** 5R01DK116079-03
- **Recipient organization:** CARNEGIE INSTITUTION OF WASHINGTON, D.C.
- **Principal Investigator:** STEVEN A FARBER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $645,300
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976330

## Citation

> US National Institutes of Health, RePORTER application 9976330, In vivo HTS assay for novel modulators of Apolipoprotein B (5R01DK116079-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976330. Licensed CC0.

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