# Role of Clec2d-DAMP interactions in the pathophysiology of tissue injury and sepsis

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $480,896

## Abstract

Abstract:
The overall goal of this grant is to elucidate the specificity, function and role in disease pathogenesis of an
innate immune receptor (CLEC2d) that we have discovered recognizes cellular histones and HMGB1. The
importance of this project is that histones and HMGB1, when released from injured cells, at as damage-
associated molecular patterns (DAMPS) that have been implicated in the pathogenesis of a number of
important diseases, including sepsis, ischemia-reperfusion injury, toxic organ damage and autoimmunity. The
study of CLEC2d will provide insight into how these DAMPs mediate their effects and whether CLEC2d could
be a therapeutic target to block the contribution of these DAMPs to disease. The first aim will elucidate the
function of CLEC2d in innate immune cells. We will explore the hypotheses that this CLEC is important for: (a)
the direct stimulation of innate immune cells by histones and HMGB1; (2) stimulation of innate immune cells by
histoneHMGB1-associated immunostimulatory molecules (PAMPs and DAMPs), and/or (3) the clearance of
extracellular histones/HMGB1. The second aim will elucidate the role of the CLEC2d in histone/HMGB1-
mediated diseases in vivo. We will explore the hypothesis that the CLECs are needed for histone/HMGB1-
mediated pathology in vivo and the pathogenic sequelae of tissue injury and sepsis. The third aim will define
the specificity of CLEC2d, how histone modifications alter recognition and responses, and whether this
receptor recognizes other poly-basic DAMPs. Our hypotheses are that CLEC2d recognized a poly-basic
degenerate motif(s) that is shared between 5 histones, HMGB1 and some other DAMPs and is sensitive to
alternations in post-translational modifications of these DAMPs that occur in some diseases.

## Key facts

- **NIH application ID:** 10164709
- **Project number:** 5R01AI129966-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** KENNETH L ROCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,896
- **Award type:** 5
- **Project period:** 2017-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164709

## Citation

> US National Institutes of Health, RePORTER application 10164709, Role of Clec2d-DAMP interactions in the pathophysiology of tissue injury and sepsis (5R01AI129966-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164709. Licensed CC0.

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