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Immune Pathophysiology of Sickle Cell Disease

Award Number: R35HL161239
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Immune Pathophysiology of Sickle Cell Disease - Project Abstract A chronic inflammatory state is now considered a hallmark of sickle cell disease (SCD) resulting from ongoing hemolytic insult to the underlying vasculature and repeated cycles of vaso-occlusion crisis (VOC). Transfusions remain a cornerstone treatment for patients with SCD, but unlike other transfused patient populations, a higher proportion (20-50%) of patients with SCD develop alloantibodies with potentially life-threatening sequalae. These include poorly understood delayed transfusion reactions (DHTRs) whose occurrence, as well as clinical progression from mild to severe, is unpredictable. A long-standing interest of our research program has been to understand the underling immune mechanisms leading to SCD complications including VOC and transfusion complications. Our studies have uncovered an underappreciate role of circulating monocytes and the innate immune response to hemolysis, a hallmark of SCD, in transfusion complications including alloimmunization and DHTRs. Our projected studies as part of this R35 will be focused on innate immune cellular pathways that magnify the inflammatory SCD state versus the cells' heme protective pathways such as the heme detoxifying key enzyme heme oxygenase 1 in alloimmunization and in the development of DHTRs. Our laboratory has also identified a novel function for a subset of circulating monocytes, referred to as patrolling monocytes (PMo), in their ability to scavenge and remove damaged endothelium and endothelial-attached sickle RBCs. The discovery of a novel mechanism of action of PMo in SCD offers a paradigm shift in our understanding of VOC and opens up the possibility that PMos can be manipulated to prevent painful VOC. An objective of the proposed studies in this R35 is to understand the mechanisms by which PMo protect SCD vasculature and how they are affected both functionally and numerically during a vaso-occlusive event with the goal to help establish their role in VOC pathophysiology, and their potential as a therapeutic target for VOC. As we have done in the past, all the proposed studies for both objectives will combine the use of in vivo mouse models, in vitro human model systems, and patient samples to mechanistically dissect in a rigorous manner how specific immune cell types and molecular pathways contribute to SCD alloimmunization and VOC. Altogether, we believe that our laboratory's approach of integrating studies in humans and experimental models to mechanistically dissect immune pathways that regulate SCD complications is likely to be impactful and generate novel findings in areas critical to the NHLBI scientific mission.


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 = $828,377 )
2025	2025	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	4	11/15/2024	NON-COMPETING CONTINUATION	$828,377
														Subtotal = $828,377

Issue Date FY: 2024 ( Subtotal = $902,011 )
2024	2024	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	3	6/12/2024	NON-COMPETING CONTINUATION	$73,634
2024	2024	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	3	12/6/2023	NON-COMPETING CONTINUATION	$828,377
														Subtotal = $902,011

Issue Date FY: 2023 ( Subtotal = $920,420 )
2023	2023	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	2	3/2/2023	NON-COMPETING CONTINUATION	$92,043
2023	2023	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	2	12/28/2022	NON-COMPETING CONTINUATION	$828,377
														Subtotal = $920,420

Issue Date FY: 2022 ( Subtotal = $846,806 )
2022	2022	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	1	2/25/2022	NEW	$846,806
														Subtotal = $846,806

Grand Total All Awards = $3,497,614

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Immune Pathophysiology of Sickle Cell Disease

Award Number: R35HL161239

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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