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Functional genetics of tissue factor in bleeding and thrombotic risk

Award Number: DP5OD028129
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Functional genetics of tissue factor in bleeding and thrombotic risk - Project Summary/Abstract Tissue factor (TF) is the primary initiator of blood coagulation in vivo and is required to ensure hemostasis following injury. However, inappropriate TF procoagulant activity underlies substantial human suffering, including that due to myocardial infarction (MI), venous thromboembolism (VTE), stroke, and sickle cell disease. Because the cellular contribution of TF is not captured in any routine clinical assay of blood coagulation, the machinery influencing TF expression and procoagulant activity remains largely unknown. Our central hypothesis is that cellular TF and its modifiers contribute to the substantial unexplained heritability of hemostatic and thrombotic disorders, including VTE, MI, and stroke. To achieve this goal, we will intersect functional genetic and human genetic approaches to identify modifiers that contribute to TF-dependent heritability of bleeding and clotting risk. TF (“factor III”) is the only coagulation factor for which a hereditary deficiency has not been described, but in Aim 1 we will study a kindred with a bleeding diathesis in association with heterozygous TF deficiency using protein biochemistry, CRISPR-edited induced pluripotent stem cells (iPSCs) differentiated into endothelial and vascular smooth muscle cells not accessible in humans, and genetically modified mice via intravital microscopy following vascular injury; importantly, these efforts provide proof of concept that modifiers reducing TF expression by 50% can influence bleeding risk in vivo. In Aim 2, we will use an arrayed loss-of-function screen at genome-scale to identify modifiers of TF cell surface expression and procoagulant activity and intersect these findings with expression quantitative trait loci and existing population data capturing common and rare human genetic variation to identify areas of intersection, offering a generalizable strategy to use a functional screen to move beyond genetic association towards causation and mechanism. Modifiers likely contributing to TF-dependent heritability of bleeding and clotting risk will be mechanistically evaluated at scale using a custom CRISPR array and then evaluated in iPSCs, mice, and, where possible, humans. In Aim 3, we will study as a representative example one such discovery, an E3 ubiquitin ligase that strongly negatively regulates TF protein stability and procoagulant activity, employing cell biology, biochemistry, rodent models, and human genetics to mechanistically demonstrate how human genetic variation may contribute to VTE risk. Our findings will highlight the critical but clinically unmeasured contribution of cellular TF to the pathogenesis and inheritance of broadly defined hemorrhagic and thrombotic diseases. The findings will have immediate translational potential for diagnostics able to capture this risk to guide personalized treatment and suggest promise for new anticoagulant therapies with reduced bleeding risk that selectively target pathways leading to inappropriate TF procoagulant activity.


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 = $437,500 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	001	5	8/22/2023	NON-COMPETING CONTINUATION	$437,500
2023	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	000	4	8/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $437,500

Issue Date FY: 2022 ( Subtotal = $437,500 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	000	4	8/31/2022	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2021 ( Subtotal = $437,500 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	001	3	9/13/2021	NON-COMPETING CONTINUATION	$437,500
2021	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	000	2	12/2/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $437,500

Issue Date FY: 2020 ( Subtotal = $437,500 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	000	2	8/28/2020	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2019 ( Subtotal = $437,500 )
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Research Support	000	1	9/16/2019	NEW	$437,500
														Subtotal = $437,500

Grand Total All Awards = $2,187,500

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Functional genetics of tissue factor in bleeding and thrombotic risk

Award Number: DP5OD028129

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/16/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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