Thursday, January 1, 2026 1/1/2026

CD11c as a novel target to improve neutrophil effector functions and sepsis outcome

Award Number: R01GM148392
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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CD11c as a novel target to improve neutrophil effector functions and sepsis outcome - Project Summary/ Abstract Sepsis remains to be associated with a high mortality of 20 to 30% with annual cost of $24 billion, accounting for nearly one-fifth of the total aggregate costs in all the hospitalizations in the United States. Current sepsis management is supportive. Therefore, identifying therapeutic approaches is an urgent task to improve the outcome of sepsis. Neutrophils eradicate microbes as the first-line defense innate immune cells. In sepsis, exaggerated de novo neutrophil production called emergency granulopoiesis occurs mainly via G-CSF production. However, immature neutrophils are also released into a circulation to meet a high demand for neutrophil number, but they have less antimicrobial defense functions, leading to worse host defense in septic patients. G-CSF itself does not trigger full neutrophil maturation. Thus, an intervention to attain the enhancement of neutrophil maturation is critical in sepsis for better host defense. Integrin CD11c was considered a sensitive marker to differentiate sepsis from systemic inflammatory response syndrome. We previously showed that CD11c KO mice had worse survival in the polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery, indicating the critical role of CD11c in sepsis. There has been a paucity of research about its functional role in vivo. We unexpectedly identified that CD11c was expressed in the bone marrow (BM) neutrophils (largely intracellular) and its deficiency was associated with less BM neutrophil maturation. In a mouse model to recapitulate emergency granulopoiesis, mature neutrophils were released in significantly less quantity in CD11c KO mice compared to wild type (WT) mice, further suggesting its importance in neutrophil maturation. We created CD11c constitutively active knock-in (KI) mice, which demonstrated to have more mature neutrophils in the BM in a steady-state condition and during infection with better bacterial eradication and outcomes. In addition, our in vitro neutrophil maturation experiments using primary murine CD11c KO neutrophils or HL-60 cells devoid of CD11c by CRISPR/Cas9 technology showed less neutrophil maturation. Based on these results, we hypothesized that CD11c activity would significantly regulate the degree of neutrophil maturation in a steady state and emergency granulopoiesis in a cell-intrinsic manner. Our preliminary data suggested that CD11c would also regulate a subset of neutrophil effector functions irrelevant of maturation. Thus, we will determine the role of CD11c in neutrophil maturation and effector functions in a steady state and sepsis in Aim 1 and Aim 2. Because IQGAP1 was suggested to be a binding partner for CD11c, its role will also be studied to delineate the mechanism of how CD11c regulates neutrophil maturation and effector functions. Studies will be done by using human sepsis subjects and murine models. Because there are no CD11c small molecule agonists and antagonists available, we will screen them in Aim 3. Upon the completion of the proposal, we expect that we would solidify that CD11c would be a critical regulator of neutrophil maturation and effector functions for a therapeutic intervention in sepsis.


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 = $342,451 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	12/17/2025	NON-COMPETING CONTINUATION	$342,451
														Subtotal = $342,451

Issue Date FY: 2025 ( Subtotal = $381,984 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	3	8/18/2025	NON-COMPETING CONTINUATION	$38,199
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	12/20/2024	NON-COMPETING CONTINUATION	$343,785
														Subtotal = $381,984

Issue Date FY: 2024 ( Subtotal = $386,433 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	6/10/2024	NON-COMPETING CONTINUATION	$38,642
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	12/18/2023	NON-COMPETING CONTINUATION	$347,791
														Subtotal = $386,433

Issue Date FY: 2023 ( Subtotal = $389,400 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/18/2023	NEW	$389,400
														Subtotal = $389,400

Grand Total All Awards = $1,500,268

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CD11c as a novel target to improve neutrophil effector functions and sepsis outcome

Award Number: R01GM148392

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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