Thursday, November 21, 2024 11/21/2024

Kidney Microphysiological Analysis Platforms (MAP) to Optimize Function and Model Disease

Award Number: UH3TR002155
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Coronavirus disease 2019 (COVID-19) has reached pandemic proportions. Pulmonary and kidney disease are highly prevalent serious consequences of infection with SARS-CoV-2. Kidney Injury Molecule-1 (KIM-1) was identified by Drs Bonventre and Ichimura as the most upregulated protein in the injured kidney proximal tubule. KIM-1, also called TIM-1, is a receptor for hepatitis A, Ebola, Dengue and possibly SARS-CoV1 viruses. We hypothesize that KIM-1 is a receptor for SARS-CoV-2 both in renal tubule epithelial cells and in airway epithelial cells and that JB1, our newly discovered small molecule inhibitor of KIM-1, and/or nanodisc- incorporated KIM-1 ectodomain can be prophylactic and therapeutic agents for COVID-19. We also hypothesize that we can use the high-affinity binding of KIM-1 and ACE2 to the virus to create novel diagnostic devices for the virus. In Specific Aim 1 we will characterize the role of KIM-1 in promoting SARS-CoV-2 entry into kidney and lung epithelia using kidney microphysiological analysis platforms (MAPs) on chip and develop an ultrasensitive chip for the high-throughput evaluation of potential SARS-CoV-2 binding inhibitors. KIM-1 and ACE2 mediated endocytosis of SARS-CoV-2 biomimetic viruses (virosomes) will be compared in kidney and lung epithelial cells. We will evaluate the effects of KIM-1-mediated spike proteins or biomimetic virus cellular adhesion and uptake on production of paracrine factors which activate endothelial cells using a kidney-lung MAP. In order to understand binding and/or uptake kinetics of SARS-CoV-2 and characterize potential inhibitors we will develop an ultrasensitive nanoplasmonic triplets-based rapid lateral flow diagnostic chip for a rapid and sensitive inhibition assay using the kidney-lung MAP. This approach can also be used for point of care diagnostic testing for the virus. In Specific Aim 2 we will evaluate the efficacy of JB1, soluble KIM-1 ectodomain and nanodisc-incorporated KIM-1 or ACE2 to inhibit binding and internalization of SARS-CoV-2 biomimetic viruses by kidney and lung cells using an integrated lung-kidney MAP on chip. Potential inhibitors will be tested to evaluate whether they compete with S-protein and/or biomimetic virus binding and reduce IL-6 production. Binding affinity and kinetics between KIM-1 variants or ACE2 either as free ectodomains or incorporated into nanodiscs and the Spike protein will be measured using MicroScale Thermophoresis (MST) and Biolayer Interferometry.


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 = -$89,781 )
2025	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	001	5	11/14/2024	NON-COMPETING CONTINUATION	-$89,781
2025	2020	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	4	10/9/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = -$89,781

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	5	9/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	4	11/7/2021	SUPPLEMENT FOR EXPANSION	-$50,670
2022	2020	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	002	4	2/18/2022	SUPPLEMENT FOR EXPANSION	$50,670
2022	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	001	4	2/2/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,006,126 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	5	7/14/2021	NON-COMPETING CONTINUATION	$1,006,126
														Subtotal = $1,006,126

Issue Date FY: 2020 ( Subtotal = $1,343,322 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	002	4	7/30/2020	NON-COMPETING CONTINUATION	$1,006,126
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	003	4	8/11/2020	SUPPLEMENT FOR EXPANSION	$251,531
2020	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	001	3	3/27/2020	EXTENSION WITH OR WITHOUT FUNDS	$85,665
2020	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	3	3/25/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $1,343,322

Issue Date FY: 2019 ( Subtotal = $1,025,876 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	National Center for Advancing Translational Sciences	000	3	9/13/2019	EXTENSION WITH OR WITHOUT FUNDS	$1,025,876
														Subtotal = $1,025,876

Grand Total All Awards = $3,285,543

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Kidney Microphysiological Analysis Platforms (MAP) to Optimize Function and Model Disease

Award Number: UH3TR002155

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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