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Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury

Award Number: R01AI173076
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/09/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury - Abstract The immune system has evolved mechanisms to recognize cell injury and in response stimulate sterile inflammation. This response contributes in important ways to both heath and disease. In this process, dying cells release Damage Associated Cell Patterns (DAMPs) that are detected by receptors on immune cells, which then trigger sterile inflammation. Histones are DAMPs that are major drivers of sterile inflammation and there is a recent growing literature implicating the release of and response to histones in the morbidity and mortality from tissue injury. Given the role of these DAMPs in the pathogenesis of disease, it is important to understand the receptors that engage these ligands and mediate their effects. Before our work, such receptors were unknown. We discovered the first cellular receptor for histones, which was the C-type lectin receptor (CLR/Clec) Clec2d. We showed that Clec2d plays an important role in innate immune responses to histones and the pathogenesis of disease in vivo. Our studies also revealed that Clec2d is not the whole story and that there must be another histone receptor(s) in mice that contributes to responses and disease. Moreover, human innate immune cells are similarly stimulated by histones, however when we went to translate our findings to humans, we found that the human homolog of Clec2d does not recognize histones. Therefore, there are as yet to be identified human histone receptors. Importantly, we have now discovered such novel Clec-histone receptors (CHRs) in both mice and humans and these discoveries form the basis for this grant application. We have two Aims: Aim 1 will elucidate the role of CHRs in innate immune responses to histones in vivo. We will define what innate immune cells use CHRs to sense histones in vivo, the nature of the subsequent responses, and their role in the sterile inflammatory response and pathogenic sequelae of tissue injury in vivo. The importance of this aim is that it will provide insight into disease pathogenesis and potentially identify new molecular targets for treating these conditions; and, Aim 2 will define the specificity, consequences and underlying mechanisms of histone stimulation of novel CHRs. The importance of this aim is that it will define the underlying mechanisms by which histones and their receptors trigger and regulate responses, which ultimately drive host defense and pathobiology.


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 = $593,865 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	11/25/2025	NON-COMPETING CONTINUATION	$593,865
														Subtotal = $593,865

Issue Date FY: 2025 ( Subtotal = $576,048 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	11/6/2024	NON-COMPETING CONTINUATION	$576,048
														Subtotal = $576,048

Issue Date FY: 2024 ( Subtotal = $593,865 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	2	5/13/2024	NON-COMPETING CONTINUATION	$59,387
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	10/28/2023	NON-COMPETING CONTINUATION	$534,478
														Subtotal = $593,865

Issue Date FY: 2023 ( Subtotal = $593,865 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	11/9/2022	NEW	$593,865
														Subtotal = $593,865

Grand Total All Awards = $2,357,643

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Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury

Award Number: R01AI173076

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/09/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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