Thursday, April 3, 2025 4/3/2025

Harnessing the power of experimental genetic crosses and systems genetics to probe drug resistance in malaria

Award Number: P01AI127338
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Description

Harnessing the power of experimental genetic crosses and systems genetics to probe drug resistance in malaria - ABSTRACT Genetic crosses coupled with linkage mapping have provided an outstandingly successful approach for locating the genetic determinants of biomedically important traits such as drug resistance and host specificity in P. falciparum malaria. Plasmodium crosses were originally conducted using chimpanzees, but crosses using these primates are now no longer possible. The overall goal of this Program Project grant (P01) is to leverage cutting edge technology that enables us to stage Plasmodium falciparum experimental genetic crosses and isolate large numbers of unique recombinant progeny. We do this using a human-liver chimeric mouse infused with human red blood cells (the FRG huHep/huRBC mouse). We will use this technology to address the emerging health threat posed by the emergence and spread of artemisinin resistant (ART-R) and more recently piperaquine resistant parasites. There has been much fanfare recently about the identification of coding mutations in the kelch13 gene that are strongly associated with ART-R. However, very little is known about the function of this gene and how mutations in kelch13 generate a wide range of resistance levels and fitness effects, and how these effects are compensated by other structural or regulatory changes in the genome. Furthermore, there is evidence of ART- R without mutations in kelch13, and that particular genetic backgrounds are permissive for ART-R. We will use targeted experimental genetic crosses to (i) dissect the genetic complexity of ART-R, (ii) clarify the role of kelch13, (iii) define the regulators and partner genes that control ART-R, and (iv) determine the genetic basis of emerging piperaquine resistance. The project is based in three locations (Notre Dame, Seattle and San Antonio), each with one Research Project supported by a Core facility, with an Administrative Core in Notre Dame. The three research Cores support the tasks of each of the three individual Research Projects, and rely on each other for the generation of progeny lines, sequencing and complementary data analysis. Each Research Project has its own stand- alone research questions, but the flow of information and reagents among projects significantly enhances the potential for discovery that fully leverages the P01 framework. Genetic crosses will be conducted by Core A, while RP01 will increase our understanding of the fundamental aspects of sexual recombination and Mendelian genetics in P. falciparum, allowing us to further optimize methods for generating recombinant progeny. The recombinant progeny will be characterized for drug resistance and competitive growth phenotypes by RP02 and for variation in transcript, protein and metabolite abundance by RP03, with support from Core C. The phenotype, sequence and systems genetic data will be integrated by Core B, which will both conduct analyses and ensure that the archived data will be accessible to all three Research Projects.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	5	2/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $2,430,648 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	001	6	4/25/2024	COMPETING CONTINUATION	$2,430,648
2024	2021	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	5	4/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,430,648

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	5	7/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $2,004,499 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	5	7/26/2021	NON-COMPETING CONTINUATION	$2,004,499
														Subtotal = $2,004,499

Issue Date FY: 2020 ( Subtotal = $2,366,515 )
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	4	7/14/2020	NON-COMPETING CONTINUATION	$2,366,515
														Subtotal = $2,366,515

Issue Date FY: 2019 ( Subtotal = $2,366,515 )
2019	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	3	8/6/2019	NON-COMPETING CONTINUATION	$2,366,515
														Subtotal = $2,366,515

Issue Date FY: 2018 ( Subtotal = $2,342,378 )
2018	2018	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	2	7/26/2018	NON-COMPETING CONTINUATION	$2,342,378
														Subtotal = $2,342,378

Issue Date FY: 2017 ( Subtotal = $2,408,349 )
2017	2017	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	1	7/31/2017	NEW	$2,408,349
														Subtotal = $2,408,349

Grand Total All Awards = $13,918,904

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Harnessing the power of experimental genetic crosses and systems genetics to probe drug resistance in malaria

Award Number: P01AI127338

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer