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3D human-based microvessel bed for the study of Plasmodium falciparum interacting with vessel wall

Award Number: R01HL130488
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2020

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3D human-based microvessel bed for the study of Plasmodium falciparum interacting with vessel wall - DESCRIPTION (provided by applicant): Cytoadhesion of Plasmodium falciparum infected erythrocytes is a major virulence determinant that enables parasites to sequester from blood circulation by binding to the endothelial lining of blood vessels and avoid spleen-dependent killing mechanisms. Whereas infected erythrocytes sequester in a variety of microvascular beds, cerebral malaria is a life-threatening disease complication that is associated with massive sequestration in brain microvessels. Cerebral malaria is accompanied by endothelial activation, blood-brain barrier disruption and fibrin thrombi at sites of infected erythrocyte sequestration. While progress has been made in understanding the binding properties of infected erythrocytes, critical questions remain unanswered about the mechanisms of cerebral malaria pathogenesis. Binding of P. falciparum- infected erythrocytes is mediated by the large and diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We recently showed that severe malaria is associated with a distinct subset of PfEMP1 variants that binds to endothelial protein C receptor, an important regulator of blood clotting and endothelial activation. Our preliminary findings suggest that parasites may impair EPCR function and lead to cerebral malaria complications. However, a significant barrier to investigating disease mechanisms in human cerebral malaria is the inaccessibility of the brain. This project will exploit new advances in microvascular engineering technology in the study of human cerebral malaria. By building a human brain microvascular model, we will: 1. Characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to human brain endothelial cells and other microvascular beds using in vitro 3D human microvascular systems. 2. Determine the consequent changes on the barrier and thrombogenic properties of the vessel wall. 3. Determine host signaling pathways engaged by the infected erythrocyte-endothelial activation that are associated with endothelial dysfunction or protection. The success of the project will shed light on the pathogenic mechanisms associated with cerebral malaria and may guide potential therapeutic development.


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: 2023 ( Subtotal = -$35,401 )
2023	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	000	5	2/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$35,401
														Subtotal = -$35,401

Issue Date FY: 2022 ( Subtotal = $35,400 )
2022	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	000	5	10/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,400
														Subtotal = $35,400

Issue Date FY: 2021 ( Subtotal = -$35,401 )
2021	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	000	5	12/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$35,401
														Subtotal = -$35,401

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	005	5	7/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	4	6/24/2019	NON-COMPETING CONTINUATION	-$464,949
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	001	5	5/31/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$99,884
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Blood Diseases and Resources Research	004	5	6/24/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$564,833
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	4	5/31/2019	NON-COMPETING CONTINUATION	-$99,884
2019	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	3	6/24/2019	NON-COMPETING CONTINUATION	-$99,884
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $564,833 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	4	5/23/2018	NON-COMPETING CONTINUATION	$564,833
														Subtotal = $564,833

Issue Date FY: 2017 ( Subtotal = $564,833 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	3	6/16/2017	NON-COMPETING CONTINUATION	$564,833
														Subtotal = $564,833

Issue Date FY: 2016 ( Subtotal = $550,536 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	5/19/2016	NON-COMPETING CONTINUATION	$550,536
														Subtotal = $550,536

Issue Date FY: 2015 ( Subtotal = $572,786 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	1	9/11/2015	NEW	$572,786
														Subtotal = $572,786

Grand Total All Awards = $2,217,587

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3D human-based microvessel bed for the study of Plasmodium falciparum interacting with vessel wall

Award Number: R01HL130488

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2020

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