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Mechanisms of Marginal Zone Depletion in Sickle Cell Spleen Tissue

Award Number: R03HL183274
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Mechanisms of Marginal Zone Depletion in Sickle Cell Spleen Tissue - PROJECT SUMMARY Sickle cell disease (SCD) is a devastating inherited hemolytic anemia that affects millions of people worldwide. Over 500,000 infants are born with SCD annually and the majority die before 5 years of age due to spleen dysfunction. In studies conducted with my K23 award, we determined that spleen damage in SCD impacts adaptive immunity. We identified an age-related decline in unswitched memory B cells (UMBC), the peripheral blood equivalent to splenic marginal zone B cells, and a corresponding increase in naïve B cells compared to children without SCD. Children with SCD/very low UMBC had >2-fold lower splenic expression of three genes important for B cell differentiation compared to SCD/low UMBC: IL21R, PF4, and CX3CR1. Expression of genes for ligands that activate B cell differentiation, DLL1 and JAG1, were significantly higher in children with SCD/very low UMBC compared to SCD/low UMBC. These data suggest that IL21R, PF4, CX3CR1, DLL1, and JAG1 have a role in the mechanism of MZB loss, B cell differentiation, and adaptive immunity in SCD. There is a critical gap in knowledge about the mechanisms of adaptive immune dysfunction in the spleen, and how to target these pathways to prevent life-threatening infections and autoimmunity in SCD. Our purpose of this limited R03 award is to prioritize genes important for B cell development in SCD spleen for future clinical and mechanistic studies. Our central hypothesis is that SCD alters expression of key genes important for B cell differentiation, leading to low UMBCs and higher naïve B cell counts. Aim 1. Develop an ex vivo system to investigate the role of IL21R, PF4, and CX3CR1 in B cell development in SCD. We will validate our findings with RNA sequencing of additional spleen samples. We will measure serum IL21, PF4, and fractalkine (the ligand for CX3CR1) by ELISA in SCD and correlate levels with B cell subsets. We will differentiate CD34+ stem cells into B cells to compare expression and activity of IL21R, PF4, and CX3CR1 in SCD- versus non-SCD-derived B cell subsets using flow cytometry and transcriptomic approaches. Aim 2. Determine the role of DLL1 and JAG1 in B cell differentiation in the spleen in SCD. We will use spatial transcriptomics to localize DLL1 and JAG1 signaling in human spleen tissue. We will use imaging flow cytometry to compare interactions between cells that express DLL1 and JAG1 and B cells in spleen tissue from patients with and without UMBC loss. We will validate the Townes SCD mouse model as a tool to examine how inflammatory stimuli influence the expression of Dll1 and Jag1 in the spleen in vivo. Impact: I expect my research will lead to significantly improved outcomes for SCD by identifying novel pathways in adaptive immunity that contribute to complications in SCD. Enhanced understanding of these pathways will yield new targets urgently needed for druggable disease modification. Within two years, I will have necessary tools and preliminary data to apply for independent funding through an R01 or similar mechanism.


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 = $240,707 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	1	5/5/2026	NEW	$240,707
														Subtotal = $240,707

Grand Total All Awards = $240,707

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Mechanisms of Marginal Zone Depletion in Sickle Cell Spleen Tissue

Award Number: R03HL183274

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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