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Investigating dysregulation of hematopoietic stem cell support in sickle cell disease mesenchymal stromal cells

Award Number: F31HL170678
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigating dysregulation of hematopoietic stem cell support in sickle cell disease mesenchymal stromal cells - Project Summary Sickle cell disease (SCD) is one of the most common hemoglobinopathies in the world. It results from a mutation in the hemoglobin β gene which causes hemoglobin polymerization, leading to chronic hemolysis, inflammation, damage to organs, and increased early morbidity. SCD pathophysiology can damage and stress the bone marrow microenvironment and resident hematopoietic stem cells (HSCs), as evidenced in our pilot studies revealing fewer functional HSCs in the bone marrow of both mice and individuals with SCD. Sinusoidal and arterial vascular networks in the SCD bone marrow are also significantly disrupted. Furthermore, SCD is marked by decreased numbers of mesenchymal stromal cells (MSCs), a heterogeneous cell population that functions as critical regulators of HSC self-renewal and differentiation. We observed significant changes to MSC transcriptional profiles in SCD and identified three aberrant SCD MSC phenotypes: 1) increased SCD MSC cell cycling, 2) increased secretion of inflammatory cytokines, and 3) decreased HSC support. The transcription factor Early B Cell Factor 3 (EBF3) is a standout differentially expressed gene in SCD MSCs and a known regulator of cell cycle. Loss of EBF3 in MSC subpopulations dramatically impacts bone marrow composition and HSC support. Cumulatively, these findings lead me to hypothesize that EBF3 downregulation in bone marrow MSCs during SCD causes transcriptional changes that decrease their HSC support capacity. In Aim 1, I will determine how Ebf3 downregulation is driving the changes we observe in mouse SCD MSCs via over-expression and knockdown of Ebf3 in SCD and control MSCs; I will then quantify changes to their HSC support capacity through ex vivo primary cultures and in vivo transplantation studies. In Aim 2, I will identify EBF3 transcriptional targets and their cellular functions in control and SCD MSCs via protein- chromatin interaction studies, gene ontology analysis, and gene set enrichment analysis as well as mechanistic interrogation of Ebf3 downregulation. In Aim 3, I will investigate the translational impact of EBF3 downregulation in human SCD MSCs by again employing over-expression and knockdown systems to perturb EBF3 expression and quantify how this impacts their support of human HSCs. I will also elucidate the transcriptional targets of EBF3 in human MSCs, which has never been done before. This study will be an important first step in better understanding how transcriptional dysfunction in SCD MSCs influences HSC support, which, in turn, may be critical in the improvement of SCD curative therapies.


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	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Blood Diseases and Resources Research	000	2	6/16/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $44,974 )
2024	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Blood Diseases and Resources Research	000	2	7/19/2024	NON-COMPETING CONTINUATION	$44,974
														Subtotal = $44,974

Issue Date FY: 2023 ( Subtotal = $43,694 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Blood Diseases and Resources Research	000	1	6/29/2023	NEW	$43,694
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Blood Diseases and Resources Research	001	1	6/29/2023	NEW	$0
														Subtotal = $43,694

Grand Total All Awards = $88,668

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Investigating dysregulation of hematopoietic stem cell support in sickle cell disease mesenchymal stromal cells

Award Number: F31HL170678

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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