# Cell Death Sensing Pathways That Trigger Necroinflammation

> **NIH NIH DP5** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Therapeutic modulation of immune checkpoints has emerged as a transformative new paradigm in the
treatment of cancer. This development has triggered immense interest in targeting new co-regulatory pathways
to amplify the early success of immunotherapy. A major challenge in this endeavor is the widespread
pleiotropy characteristic to immune signaling pathways. Due to the promiscuity of their ligand:receptor
interactions, co-regulatory proteins can produce multiple, often contradictory activities. This poses difficulty in
developing agents that can isolate specific pathway functions and obscures a precise understanding of the
physiology of individual receptor:ligand pairs. The LIGHT/HVEM/LTβR signaling network is a key exemplar of
this challenge. LIGHT is an immune co-stimulator that plays a crucial role in the activation and expansion of T
cells. It signals through both the Herpes virus entry mediator (HVEM) and the lymphotoxin beta receptor
(LTβR), and it is antagonized by decoy receptor 3 (DcR3). However, each of these receptors binds additional
ligands besides LIGHT, resulting in a complicated and interconnected signaling network. Here, we propose to
leverage our expertise in structure-guided protein engineering to develop and characterize LIGHT variants that
can uncouple the disparate activities of the LIGHT/HVEM/LTβR pathway. We will knock-in these “biased”
alleles into transgenic mice to study individual pathway interactions in vivo and in parallel, we will assess the
therapeutic potential of biasing LIGHT activity in models of immunotherapy. In sum, this proposal will provide
insight into a pivotal immunoregulatory pathway, candidate molecules for therapeutic development, and new
approaches for targeting pleiotropic checkpoint receptors.

## Key facts

- **NIH application ID:** 9999962
- **Project number:** 5DP5OD023088-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Aaron Michael Ring
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2016-09-16 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999962

## Citation

> US National Institutes of Health, RePORTER application 9999962, Cell Death Sensing Pathways That Trigger Necroinflammation (5DP5OD023088-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999962. Licensed CC0.

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