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The bone marrow extracellular matrix: scaffold of hematopoiesis

Award Number: K01OD025290
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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The bone marrow extracellular matrix: scaffold of hematopoiesis - ABSTRACT This proposal addresses the urgent need to understand disease mechanisms in Primary Myelofibrosis (PMF). PMF is a disease with a dismal prognosis. The only potentially curative therapy, allogeneic stem cell transplantation, is a high-risk procedure, with a mortality rate of at least 50%. Myelofibrosis is characterized by excessive production of extracellular matrix (ECM), the fibers in bone marrow, which leads to a progressive failure in blood cell production. A number of gene mutations, including JAK2V617F, have been reported in PMF. While it is thought that hematopoietic cells carrying gene mutations abnormally proliferate and secrete factors that stimulate stromal cells to produce ECM excessively, inhibition of JAK2 only partially improves disease outcomes, and complementary therapies that specifically target ECM production are not currently available. Dependence on the prevalent hypothesis, with its focus on gene mutations, is a critical barrier to progress in the field. This project proposes instead to address the problem from the ECM angle. Building on our published and preliminary studies with mouse and human samples, the central hypothesis of this proposal is that abnormal activation of integrins (adhesive molecules that mediate cell attachment to ECM) facilitates proliferation of PMF cells. As PMF proliferation arises from interaction between ECM and integrins, the question is whether proliferation is triggered by an abnormality in ECM formation or by direct integrin activation. Thus, I will explore two potential mechanisms behind this abnormal integrin activation, asking whether: (1) abnormally high ECM production occurs in the vascular niche, where PMF cells develop, and (2) Lysyl oxidase (LOX), an ECM enzyme upregulated in PMF, activates integrins in PMF through post-translational modification. These studies will be performed on the most representative mouse model of human PMF, mice transgenic for the JAK2V617F mutation. Effects of integrins on cell proliferation in PMF will be determined by blocking integrin function with antibodies and by deleting integrin genes using CRISPR/Cas9. I will use 3D confocal imaging and advanced computational analysis to determine the spatial distribution of cells, ECM, and vasculature in myelofibrotic bone marrow, clarifying the mechanisms of ECM production by detailed morphological analysis of the vascular niche. Proteomic analysis of post-translational modifications will be performed on integrins to determine specific lysine residues oxidized by LOX, which has implications on the development of therapies targeting integrins or LOX. This is a Career Development Award, and the PI of this application will have the mentorship of investigators with expertise in the field for the execution of the project. The project builds on previous experience of the PI in malignant hematology. The training and the expertise acquired during this award will provide a foundation for a successful independent career for the PI of this project.


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 = $0 )
2025	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	5	6/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $186,169 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	001	5	7/29/2023	SUPPLEMENT FOR EXPANSION	$87,000
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	5	1/14/2023	NON-COMPETING CONTINUATION	$99,169
														Subtotal = $186,169

Issue Date FY: 2022 ( Subtotal = $105,120 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	4	2/17/2022	NON-COMPETING CONTINUATION	$94,607
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	001	4	5/17/2022	NON-COMPETING CONTINUATION	$10,513
														Subtotal = $105,120

Issue Date FY: 2021 ( Subtotal = $106,280 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	001	3	3/13/2021	NON-COMPETING CONTINUATION	$10,628
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	3	2/2/2021	NON-COMPETING CONTINUATION	$95,652
														Subtotal = $106,280

Issue Date FY: 2020 ( Subtotal = $106,856 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	001	2	3/11/2020	NON-COMPETING CONTINUATION	$10,686
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	2	1/11/2020	NON-COMPETING CONTINUATION	$96,170
														Subtotal = $106,856

Issue Date FY: 2019 ( Subtotal = $106,383 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Research Infrastructure Programs	000	1	1/16/2019	NEW	$106,383
														Subtotal = $106,383

Grand Total All Awards = $610,808

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The bone marrow extracellular matrix: scaffold of hematopoiesis

Award Number: K01OD025290

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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