# Dissecting the genetic complexity of artemisinin resistance

> **NIH NIH P01** · UNIVERSITY OF NOTRE DAME · 2021 · $394,278

## Abstract

ABSTRACT
The recently identified kelch13 gene is an important marker of artemisinin resistance (ART-R) in malaria and
has been linked to the slow-clearance rate (CR) clinical phenotype as well as treatment failures. In spite of this
exciting discovery of a major gene affecting the trait, there are several indications that additional (or alternative)
genes and gene interactions contribute to both the level of resistance, as measured by slow clearance times in
the clinic and ring stage survival in the laboratory. Understanding the detailed functional role of various kelch13
mutants, their broader biological roles and functional partners, and their impact on fitness presents strategic
hurdles to understanding and slowing the evolution and spread of ART-R.
Recognizing that the phenotypic effect of a major resistance gene resides in a co-evolved whole-genome
context, we will use quantitative trait locus (QTL) mapping combined with intensive and precise phenotyping
across a set of eight inter-related experimental crosses constructed using our novel FRG huHep/huRBC mice
We will use this that determine
resistance and/or susceptibility to artemisinin and to partner drugs such as piperaquine and lumefantrine and
to identify drug targets and susceptibility determinants for a wide range of compounds. In addition, we will
examine the relationship between levels of ART-R and competitive growth in RBCs as a surrogate measure of
fitness to identify the factors that will influence the spread of malarial resistance in African populations.
to dissect this biological complexity. approach to find genes and pathways
To identify the genes and pathways that influence the origins and spread of resistance we will (i)
map the
genetic determinants of ART-R to test our hypothesis that a complex genetic architecture and multiple genes
are involved in ART-R, (ii) map genetic determinants of susceptibility to 24 antimalarial drugs, including the
partner drugs of ART, piperiquine, along with antimalarial drugs targeting a wide range of biological processes
and a set of candidate drugs for which the drug target is not known and, (iii) map the impact of ART-R on
competitive growth using small volume head-to-head competitive-growth outcomes to compute a `relative
fitness index' quantitative score for QTL mapping.

## Key facts

- **NIH application ID:** 10216648
- **Project number:** 5P01AI127338-05
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Michael T Ferdig
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,278
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216648

## Citation

> US National Institutes of Health, RePORTER application 10216648, Dissecting the genetic complexity of artemisinin resistance (5P01AI127338-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216648. Licensed CC0.

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