# Insulin-like signaling in parasitic nematode development

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $402,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Parasitic nematodes infect roughly 20% of the world's population and exact an enormous toll in
human illness. Most of these parasites infect their hosts as developmentally arrested infective third-
stage larvae (iL3) that resume development once they enter the host. Drawing upon findings in
Caenorhabditis elegans, we have shown that the parasitic nematode Strongyloides stercoralis has
significantly modified insulin-like (ILS) and steroid-nuclear hormone receptor (NHR) signaling to
regulate iL3 development during the infective process. In this renewal application, we propose to
expand our studies of regulation of iL3 development and morphogenesis by ILS and NHR signaling in
S. stercoralis, deploying our new method for CRISPR/Cas9 mutagenesis to unambiguously assess
gene function and RNAseq to determine transcriptomic changes resulting from knockout of key
signaling elements. Specific Aim 1 asks whether ILS regulates formation and development of L3i, and
what genes in S. stercoralis are regulated by ILS downstream. To this end, we will knock out Ss-daf-
16, which encodes an ILS-regulated transcription factor and Ss-daf-2, which encodes the insulin-like
receptor kinase in S. stercoralis. We will subject knockout worms to RNAseq to ascertain global
transcriptional changes and specific ones involving cytochrome P450 genes that could act in
biosynthesis of Ss-DAF-12 NHR ligands. Aim 2 will assign functions to insulin-like peptides (ILPs) in
S. stercoralis as agonists or antagonists of ILS by expressing them from transgenes designed to alter
temporal patterns of ilp transcription in the worms. Aim 2 will also determine whether Ss-DAF-12 NHR
signaling feeds back to positively regulate ILS by enhancing expression of agonistic ILPs in S.
stercoralis. Aim 3 will employ vivo and in vitro studies to test the hypothesis that Ss-DAF-12 NHR
signaling regulates lifespan in S. stercoralis, lengthening it in free-living adults and shortening it in
parasitic females. All three aims will contribute to future development of much needed new
anthelmintics targeting ILS and NHR signaling in parasitic nematodes. Elucidating functional links
between these pathways will enable new combination therapies that target both pathways, acting
additively or synergistically to block development and accelerate death and expulsion of adult worms.

## Key facts

- **NIH application ID:** 10297840
- **Project number:** 5R01AI050668-17
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** De'Broski R Herbert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2002-04-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297840

## Citation

> US National Institutes of Health, RePORTER application 10297840, Insulin-like signaling in parasitic nematode development (5R01AI050668-17). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10297840. Licensed CC0.

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