Wednesday, March 18, 2026 3/18/2026

The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation

Award Number: R01HL151494
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation - The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation Abstract Thrombocytopenia is a major clinical problem encountered in multiple conditions, and severe thrombocytopenia (platelet counts <50 x 10^9/L) can lead to life threatening bleeding. Current treatment options have severe side effects, are in limited supply, involve blood products, and the platelet response typically takes up to 12 days. Therefore, there is an urgent need to identify new thrombopoietic agents that increase platelet counts for patients. In many inflammatory conditions platelet counts rise, resulting in thrombocytosis, but what initiates this platelet up-regulation is not well understood. Our lab uses inflammation as a model of exacerbated thrombopoiesis that results in differences in platelet quality and quantity in order to 1) gain a better understanding of the basic biology of megakaryocyte (MK) maturation their production of platelets, 2) identify thrombopoietin (TPO) independent pathways of MK maturation, and 3) determine ways to reduce platelet-related morbidity and mortality in inflammation. We have discovered a novel regulator of MK maturation during inflammation: platelet-derived extracellular vesicles (PEVs) in the bone marrow. Our preliminary data indicate that platelets package and shed MVs in an agonist-specific mechanism dependent on Rho GTPase signaling; the mechanism of Rho-mediated regulation of PEV formation and packaging will be explored in Aim 1. We also found that PEVs enter the bone marrow from the plasma, and bind to and are endocytosed by MKs both in vitro and in vivo. In Aim 2, we will examine how platelet-derived MVs interact with MKs. Specifically, we will determine the mechanisms by which they bind to and are internalized by MKs and how their cargo transferred. In inflammatory conditions such as SLE, ongoing platelet activation increases levels of circulating PEVs. These PEVs deliver disease-related changes from the plasma milieu directly to MKs in the bone marrow, reprogramming the MKs to make more pathogenic platelets. In Aim 3, we will identify the PEV factors that alter MK gene expression and platelet content in SLE. Successful completion of the proposed experiments will, for the first time, provide a detailed roadmap of how PEVs alter the hematopoietic environment in the setting of inflammatory disease. The insights gained may identify novel therapeutic targets that (i) alter PEV poduction independent of platelet activation (Aim 1), (ii) hijack the PEV/MK interaction to alter MK maturation (Aim 2), and (iii) inhibit pathologic MK reprogramming during SLE and other inflammatory diseases (Aim 3).


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: 2026 ( Subtotal = $0 )
2026	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	1/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $577,271 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	5	8/5/2025	NON-COMPETING CONTINUATION	$57,725
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	3/10/2025	NON-COMPETING CONTINUATION	$519,546
														Subtotal = $577,271

Issue Date FY: 2024 ( Subtotal = $565,731 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	4	6/17/2024	NON-COMPETING CONTINUATION	$46,181
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	3/25/2024	NON-COMPETING CONTINUATION	$519,550
														Subtotal = $565,731

Issue Date FY: 2023 ( Subtotal = $577,277 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	3/23/2023	NON-COMPETING CONTINUATION	$577,277
														Subtotal = $577,277

Issue Date FY: 2022 ( Subtotal = $577,277 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	4/25/2022	NON-COMPETING CONTINUATION	$577,277
														Subtotal = $577,277

Issue Date FY: 2021 ( Subtotal = $577,277 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	4/16/2021	NEW	$519,546
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	1	6/23/2021	NEW	$57,731
														Subtotal = $577,277

Grand Total All Awards = $2,874,833

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The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation

Award Number: R01HL151494

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/20/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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