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New strategies to study malaria-induced acute kidney injury

Award Number: SC2GM144168
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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New strategies to study malaria-induced acute kidney injury - PROJECT SUMMARY Malaria-induced acute kidney injury (MAKI) is one of the most severe complications of malaria and the strongest indicator of death in both adults and children. The impact of this specific complication has been largely under-recognized, and its study neglected. There is a lack of suitable model systems for elucidating the mechanisms that lead to renal impairment during malaria infection. The current gap in knowledge is impeding ef- forts to develop accurate diagnoses and effective therapies to treat MAKI. There is, therefore, a critical need to develop experimental models to study the molecular mechanisms of MAKI. The long-term goal of this study is to develop new therapies for MAKI and identify early and accurate biomarkers of MAKI, to better diagnose and treat this disease. The overall objectives in this application are to (i) establish the scientific framework needed to study MAKI in vitro and in vivo and (ii) determine the molecular mechanism(s) by which malaria parasites induce acute kidney injury. The central hypothesis is that rupture of P. falciparum-infected red blood cells (Pf- iRBCs) releases components that directly promote acute tubular necrosis (ATN)—the hallmark of MAKI. The rationale that underlies the proposed research is that establishing the foundation for MAKI basic research and unveiling the molecular mechanisms that promote renal impairment in malaria will facilitate progress towards more sensitive diagnoses and effective treatments for MAKI. The central hypothesis will be tested by pursuing two specific aims: 1) Develop a physiological mouse model of MAKI to identify the molecular pathways leading to ATN; and 2) Identify molecular mechanisms of MAKI using in vitro assays. Under the first aim, mice will un- dergo renal surgery before infection with Plasmodium-rodent spp. The renal function will be evaluated by measuring urine output, glomerular rate filtration, blood urea nitrogen, serum creatinine levels and expression of biomarkers of acute kidney injury. Kidney tissues will be harvested for analysis of cell death pathway activa- tion as well as levels of oxidative stress. For the second aim, primary human renal tubular and microvascular cells will be co-cultured using novel technology (Organ-on-a-chip) to mimic the natural architecture of the kid- ney. Cultures will be incubated with the contents released upon bursting of Pf-iRBCs to investigate the effect(s) on endothelial-epithelial barrier integrity, tubular cytotoxicity and activation of cell death pathways. The re- search proposed in this application is innovative, as it will provide the scientific community with new physiologi- cal models of MAKI. The models will not involve the use of high vertebrate animals, which makes them acces- sible for most laboratories, and unlike other attempted models, these models are specific for the human renal pathology associated with malaria. The proposed research is significant because it is expected to provide a strong scientific basis on which to advance the understanding of the signaling pathways involved in this pathol- ogy. The results of this study will contribute to the development of innovative therapies and diagnostic tests for MAKI, which will ultimately reduce malaria mortality in both adults and children.


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 = -$885 )
2025	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	250 BEDFORD PARK BLVD W	BRONX	NY	10468	BRONX	USA	Biomedical Research and Research Training	001	3	4/3/2025	NON-COMPETING CONTINUATION	$885
2025	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	250 BEDFORD PARK BLVD W	BRONX	NY	10468	BRONX	USA	Biomedical Research and Research Training	000	3	4/2/2025	NON-COMPETING CONTINUATION	-$1,770
														Subtotal = -$885

Issue Date FY: 2023 ( Subtotal = $157,171 )
2023	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	250 BEDFORD PARK BLVD	BRONX	NY	10468	BRONX	USA	Biomedical Research and Research Training	000	3	8/15/2023	NON-COMPETING CONTINUATION	$157,171
														Subtotal = $157,171

Issue Date FY: 2022 ( Subtotal = $156,050 )
2022	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	250 BEDFORD PARK BLVD	BRONX	NY	10468	BRONX	USA	Biomedical Research and Research Training	000	2	8/10/2022	NON-COMPETING CONTINUATION	$156,050
														Subtotal = $156,050

Issue Date FY: 2021 ( Subtotal = $154,534 )
2021	2021	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	250 BEDFORD PARK BLVD	BRONX	NY	10468	BRONX	USA	Biomedical Research and Research Training	000	1	9/14/2021	NEW	$154,534
														Subtotal = $154,534

Grand Total All Awards = $466,870

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New strategies to study malaria-induced acute kidney injury

Award Number: SC2GM144168

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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