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RBC-bound cell-free DNA as a predictor of acute anemia in sickle cell disease

Award Number: R01HL178546
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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RBC-bound cell-free DNA as a predictor of acute anemia in sickle cell disease - Project Summary/Abstract Sickle cell disease (SCD) is characterized by a chronic, relatively stable anemia that is punctuated by acute drops in hemoglobin. These acute anemic events are accompanied by organ damage and clinical complications including stroke, acute chest syndrome, and vaso-occlusive episodes. Factors that drive exacerbations in anemia and mechanisms by which they contribute to acute inflammatory complications and increased mortality in patients with SCD are not understood. Chronic immune activation plays a central role in the pathophysiology of SCD. Tissue damage results in the release of intracellular contents, including mitochondrial and nuclear DNA, which contribute to overall inflammation. Cell-free DNA (cfDNA) levels are elevated in the plasma of SCD patients and are associated with vaso-occlusive episodes. Recent studies have described immune functions of red blood cells (RBCs), whereby they influence overall inflammatory status through scavenging of cytokines and expression of surface receptors. The nucleic-acid sensing receptor, Toll-like receptor 9 (TLR9) is present on RBCs and binds to circulating cfDNA in patients with infection, resulting in immune activation and anemia. This process has not been explored in the chronic inflammatory background of SCD patients. We propose that excessive levels of cfDNA from cellular damage and immune activation during vaso-occlusive complications drives acute drops in hemoglobin in SCD. Our central hypothesis is that cfDNA binding to RBC- TLR9 modulates RBC clearance and immune activation in SCD and thereby contributes to the severity of acute anemic events. Using clinical samples from patients with SCD in combination with murine models, and working at the cellular and molecular levels, we aim to 1) Determine the impact of RBC-TLR9 and cfDNA on RBC clearance in SCD, and 2) Examine the contribution of RBC-TLR9 engagement on immune dysregulation in these patients. Long term goals of this project include translating gained mechanistic insights into therapies that mitigate acute drops in hemoglobin and the associated inflammatory response in patients with SCD. Moreover, our findings may reveal predictive markers to enhance understanding of patients at the highest risk of experiencing severe acute anemic events, allowing tailored therapies and ultimately improving patient outcomes. The information gained will likely be applicable not only to SCD but also other inflammatory anemias.


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 = $797,648 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Blood Diseases and Resources Research	000	1	6/3/2026	NEW	$797,648
														Subtotal = $797,648

Grand Total All Awards = $797,648

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RBC-bound cell-free DNA as a predictor of acute anemia in sickle cell disease

Award Number: R01HL178546

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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