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The Centrosome as a master controller of platelet production.

Award Number: R35HL161175
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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The Centrosome as a master controller of platelet production. - Platelets are specialized anucleate cells that play an essential role in hemostasis, angiogenesis, immunity, and inflammation. Thrombocytopenia (platelet counts <150x109/L) is a major clinical problem encountered across a number of conditions including immune (idiopathic) thrombocytopenic purpura, myelodysplastic syndromes, chemotherapy, surgery, and genetic disorders. The demand for platelets—and for an improved understanding of their mechanistic formation—is at an all-time high. This program will use a multi-prong approach to investigate megakaryocytes (MKs) to discover therapeutic strategies and molecular targets that drive proplatelet formation and increase platelet counts. MKs are precursor cells that generate platelets by remodeling their cytoplasm into beaded proplatelet processes, which function as the assembly lines for platelet production. While we know that cytoskeletal mechanics power platelet production, many questions about platelet biogenesis remain unanswered. We know that microtubule-based forces are critical for proplatelet elongation; however, there is a surprising lack of understanding of the mechanisms that trigger platelet production. We hypothesize that centrosome regulation, via super spindle formation and KIFC1 motor involvement, is critical for the initiation of platelet production. We will use a novel high-content microscopy screen to identify the small molecules and signaling pathways that drive platelet production. Using proplatelet image analysis, we will test thousands of drug molecule candidates for their ability to stimulate or inhibit platelet production; target pathway analysis, secondary screens, and dose-response curves will be established to identify compound “hits.” While we know that proplatelet protrusions extend from bone marrow, breach the endothelial barrier, and deposit platelets into the blood, we do not know how. Therefore, we will employ bio-engineering and a unique microfluidic bone marrow on-a-chip to test the idea that actin-driven megakaryocyte podosomes provide a mechanism to penetrate the endothelium. This chip will also be used to study how organelles are transported into assembling platelets under physiological conditions, and to test the hypothesis that super spindle assembly functions as a major transport hub for distributing these organelles. We will determine if vascular thiol isomerases play a role in new platelet granule biology through investigating how they are packaged, transported, and exocytosed from platelets. We expect that findings from this investigation will 1) advance the understanding of the mechanisms that initiate and regulate platelet formation, and 2) identify novel therapeutic targets and approaches to accelerate platelet production in patients with thrombocytopenia. The R35 structure is necessary given the relative immaturity of the MK field and will provide vital time and focus to expanding the current base of knowledge. This proposal will coordinate a group of collaborators, provide the field with novel data and theory, and support junior scientists with consistent mentorship and proven leadership from a laboratory with broad ranging translational experience.


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 = $1,040,760 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	4/8/2026	NON-COMPETING CONTINUATION	$1,040,760
														Subtotal = $1,040,760

Issue Date FY: 2025 ( Subtotal = $1,062,000 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	4	6/30/2025	NON-COMPETING CONTINUATION	$106,200
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	4/8/2025	NON-COMPETING CONTINUATION	$955,800
														Subtotal = $1,062,000

Issue Date FY: 2024 ( Subtotal = $1,040,760 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$84,960
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	3/25/2024	NON-COMPETING CONTINUATION	$955,800
														Subtotal = $1,040,760

Issue Date FY: 2023 ( Subtotal = $1,168,200 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	2	3/30/2023	NON-COMPETING CONTINUATION	$1,062,000
2023	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	3/27/2023	NEW	$106,200
														Subtotal = $1,168,200

Issue Date FY: 2022 ( Subtotal = $955,800 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	2/18/2022	NEW	$955,800
														Subtotal = $955,800

Grand Total All Awards = $5,267,520

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The Centrosome as a master controller of platelet production.

Award Number: R35HL161175

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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